1,3,4,8-Tetrahydro-2H-Pyrido[1,2-a]Pyrazine Derivative and Use of the Same as HIV Integrase Inhibitor

ABSTRACT

[Problem] Provided is a novel 1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine derivative or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is useful as an anti-HIV agent. 
     [Solving Means] The present invention provides a compound represented by the following formula [I] 
     
       
         
         
             
             
         
       
     
     wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

TECHNICAL FIELD

The present invention relates to a novel1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine derivative useful as ananti-HIV agent, a pharmaceutically acceptable salt thereof, and asolvate thereof. In addition, the present invention relates to apharmaceutical composition comprising the derivative or apharmaceutically acceptable salt thereof, or a solvate thereof, and apharmaceutically acceptable carrier; an anti-HIV agent, an HIV integraseinhibitor and the like, comprising the derivative or a pharmaceuticallyacceptable salt thereof, or a solvate thereof as an active ingredient;an anti-HIV agent comprising a combination of the derivative or apharmaceutically acceptable salt thereof, or a solvate thereof, and oneor more kinds of other anti-HIV active substances; and the like.

BACKGROUND ART

HIV (Human Immunodeficiency Virus (type 1)) belonging to retrovirus is acausative virus of AIDS (Acquired Immunodeficiency Syndrome).

HIV targets CD4 positive cell groups such as helper T cell, macrophageand dendritic cell and destroys these immunocompetent cells to causeimmunodeficiency.

Accordingly, a medicament that eradicates HIV in a living organism orsuppresses its growth is effective for the prophylaxis or treatment ofAIDS.

HIV possesses a bimolecular RNA gene in a shell, which is covered withan envelope protein. The RNA codes for several enzymes (protease,reverse transcriptase, integrase) characteristic of the virus and thelike. Translated reverse transcriptase and integrase are present in theshell, and protease is present inside and outside the shell.

HIV contacts and invades a host cell, causes uncoating, and releases acomplex of RNA and integrase and the like into the cytoplasm. From theRNA, DNA is transcribed by reverse transcriptase, and a full lengthdouble stranded DNA is produced. The DNA moves into the nucleus of thehost cell and is incorporated by integrase into the DNA of the hostcell. The incorporated DNA is converted to an mRNA by polymerase of thehost cell, from which mRNA various proteins necessary for forming avirus are synthesized by HIV protease and the like, and a virus particleis finally formed, which then undergoes budding and its release.

These virus specific enzymes are considered to be essential for thegrowth of HIV. These enzymes are drawing attention as the target of thedevelopment of antiviral agents, and several anti-HIV agents have beenalready developed.

For example, zidovudine, didanosine, lamivudine and the like have beenalready on the market as reverse transcriptase inhibitors, andindinavir, nelfinavir and the like as protease inhibitors.

In addition, a multiple drug combination therapy using these medicamentsin combination (to be also referred to as HAART (highly activeantiretroviral therapy)) is also used. For example, 3 agent combinationtherapy using two agents from reverse transcriptase inhibitors(zidovudine and lamivudine, or tenofovir and emtricitabine), and anon-nucleic acid reverse transcriptase inhibitor (efavirenz), or aprotease inhibitor (lopinavir, fosamprenavir or atazanavir) incombination with ritonavir, and the like is used in clinical practice,and such multiple drug combination therapy is becoming the mainstream ofthe AIDS treatment.

However, some of these medicaments are known to cause side effects suchas liver function failure, central nervous disorders (e.g., vertigo),and the like. In addition, acquisition of resistance to a medicamentcauses a problem. Even worse, emergence of an HIV that shows multipledrug resistance in a multiple drug combination therapy has been known.

Under the circumstances, a further development of a novel medicament,particularly a development of an anti-HIV agent based on a newmechanism, has been desired, wherein a development of an anti-HIV agenthaving an integrase inhibitory activity is expected, because anintegrase characteristic of retrovirus is an essential enzyme for thegrowth of HIV.

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

From the findings obtained from pharmacological studies and clinicalresults heretofore, an anti-HIV agent is effective for the prophylaxisor treatment of AIDS, and particularly a compound having an integraseinhibitory activity can be an effective anti-HIV agent.

Therefore, the present invention aims at provision of a compound havingan anti-HIV activity, particularly a compound having an integraseinhibitory activity.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt tofind a compound having an anti-HIV action, particularly a compoundhaving an integrase inhibitory action, and completed the presentinvention.

More specifically, the present invention provides the following.

-   [1] A compound represented by the following formula [I] or a    pharmaceutically acceptable salt thereof, or a solvate thereof    (sometimes to be abbreviated as “the compound of the present    invention” in the present specification):

wherein

-   R¹ is-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from    -   (i) a C₃₋₈ cycloalkyl group, and    -   (ii) a C₁₋₆ alkoxy group,-   (2) a C₃₋₈ cycloalkyl group, or-   (3) a saturated monocyclic heterocyclic group containing, besides    carbon atom, 1 to 3 hetero atoms selected from a nitrogen atom, an    oxygen atom and a sulfur atom,-   R², R³, R⁴ and R⁵ are the same or different and each is-   (1) a hydrogen atom,-   (2) a carboxyl group,-   (3) —CO—NR^(a)R^(b) wherein R^(a) and R^(b) are the same or    different and each is    -   (i) a hydrogen atom,    -   (ii) a C₁₋₆ alkyl group optionally substituted by the same or        different 1 to 5 substituents selected from the following group        B, or    -   (iii) a C₃₋₈ cycloalkyl group, or

R^(a) and R^(b) optionally form, together with the nitrogen atom bondedthereto, a saturated monocyclic hetero ring optionally containing,besides carbon atom and one nitrogen atom, 1 to 5 hetero atoms selectedfrom a nitrogen atom, an oxygen atom and a sulfur atom, and optionallysubstituted by the same or different 1 to 5 substituents selected fromthe following group B,

-   (4) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the following group A,    or-   (5) a cyano group, or-   R² and R³, or R⁴ and R⁵ optionally form, together with the carbon    atom bonded thereto,-   i) C₃₋₈ cycloalkane, or-   ii) a saturated monocyclic hetero ring containing, besides carbon    atom, 1 to 6 hetero atoms selected from a nitrogen atom, an oxygen    atom and a sulfur atom,-   wherein R², R³, R⁴ and R⁵ are not hydrogen atoms at the same time,-   R⁶ is-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 halogen atoms,-   (2) a C₁₋₆ alkoxy group,-   (3) a halogen atom, or-   (4) a C₃₋₈ cycloalkyl group,-   Y is-   (1) CH, or-   (2) a nitrogen atom,-   m is an integer of 1 to 5, and when m is an integer of 2 to 5, then    each R⁶ may be the same or different, and-   n is an integer of 1 to 3,-   group A:-   (a) —CO—NR^(A1)R^(A2)

wherein R^(A1) and R^(A2) are the same or different and each is

-   -   (i) a hydrogen atom,    -   (ii) a C₁₋₆ alkyl group optionally substituted by the same or        different 1 to 5 substituents selected from the following group        B, or    -   (iii) a C₃₋₈ cycloalkyl group, or

R^(A1) and R^(A2) optionally form, together with the nitrogen atombonded thereto, a saturated monocyclic hetero ring optionallycontaining, besides carbon atom and one nitrogen atom, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,and optionally substituted by the same or different 1 to 5 substituentsselected from the following group B,

-   (b) a hydroxyl group,-   (c) a C₁₋₆ alkoxy group,-   (d) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group,-   (e) a cyano group,-   (f) —NR^(A3)R^(A4)

wherein R^(A3) and R^(A4) are the same or different and each is

-   -   (i) a hydrogen atom,    -   (ii) a C₁₋₆ alkyl group,    -   (iii) a C₁₋₆ alkyl-carbonyl group, or    -   (iv) a C₁₋₆ alkyl-sulfonyl group, or

R^(A3) and R^(A4) optionally form, together with the nitrogen atombonded thereto, a hetero ring optionally containing, besides carbon atomand one nitrogen atom, 1 to 5 hetero atoms selected from a nitrogenatom, an oxygen atom and a sulfur atom, and optionally substituted by 1or 2 oxo groups,

-   (g) a carboxyl group,-   (h) a C₁₋₆ alkyl-sulfonyl group, and-   (i) a C₁₋₆ alkyl-carbonyl group; group B:-   (a) a hydroxyl group,-   (b) a C₁₋₆ alkoxy group,-   (c) a C₁₋₆ alkoxy-C₁₋₆ alkyl group-   (d) a C₃₋₈ cycloalkyl group, and-   (e) an oxo group.-   [2] The compound of the above-mentioned [1], wherein R¹ is a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from    -   (i) a C₃₋₈ cycloalkyl group, and    -   (ii) a C₁₋₆ alkoxy group,-   or a pharmaceutically acceptable salt thereof, or a solvate thereof.-   [3] The compound of the above-mentioned [2], wherein R¹ is a C₁₋₆    alkyl group, or a pharmaceutically acceptable salt thereof, or a    solvate thereof.-   [4] The compound of the above-mentioned [2], wherein R¹ is a C₁₋₆    alkyl group substituted by a C₃₋₈ cycloalkyl group, or a    pharmaceutically acceptable salt thereof, or a solvate thereof.-   [5] The compound of the above-mentioned [1], wherein R¹ is a C₃₋₈    cycloalkyl group, or a pharmaceutically acceptable salt thereof, or    a solvate thereof.-   [6] The compound of the above-mentioned [1], wherein one of R², R³,    R⁴ and R⁵ is —CO—NR^(a)R^(b)

wherein R^(a) and R^(b) are the same or different and each is

-   -   (i) a hydrogen atom,    -   (ii) a C₁₋₆ alkyl group optionally substituted by the same or        different 1 to 5 substituents selected from group B, or    -   (iii) a C₃₋₈ cycloalkyl group, or

R^(a) and R^(b) optionally form, together with the nitrogen atom bondedthereto, a saturated monocyclic hetero ring optionally containing,besides carbon atom and one nitrogen atom, 1 to 5 hetero atoms selectedfrom a nitrogen atom, an oxygen atom and a sulfur atom, and optionallysubstituted by the same or different 1 to 5 substituents selected fromgroup B,

-   or a pharmaceutically acceptable salt thereof, or a solvate thereof.-   [7] The compound of the above-mentioned [1], wherein one of R², R³,    R⁴ and R⁵ is a C₁₋₆ alkyl group optionally substituted by the same    or different 1 to 5 substituents selected from group A, or a    pharmaceutically acceptable salt thereof, or a solvate thereof.-   [8] The compound of the above-mentioned [1], wherein R⁶ is a halogen    atom, or a pharmaceutically acceptable salt thereof, or a solvate    thereof.-   [9] The compound of the above-mentioned [1], wherein Y is CH, or a    pharmaceutically acceptable salt thereof, or a solvate thereof.-   [10] The compound of the above-mentioned [1], wherein Y is a    nitrogen atom, or a pharmaceutically acceptable salt thereof, or a    solvate thereof.-   [11] The compound of the above-mentioned [1], wherein m is 1 or 2,    or a pharmaceutically acceptable salt thereof, or a solvate thereof.-   [12] The compound of the above-mentioned [1], wherein n is 1, or a    pharmaceutically acceptable salt thereof, or a solvate thereof.-   [13] The compound of the above-mentioned [1], which is represented    by the following formula [I-1], or a pharmaceutically acceptable    salt thereof, or a solvate thereof:

wherein

-   R¹¹ is-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from    -   (i) a C₃₋₈ cycloalkyl group, and    -   (ii) a C₁₋₆ alkoxy group, or-   (2) a C₃₋₈ cycloalkyl group, R²¹, R³¹, R⁴¹ and R⁵¹ are the same or    different and each is-   (1) a hydrogen atom,-   (2) —CO—NR^(a)R^(b)

wherein R^(a) and R^(b) are the same or different and each is

-   -   (i) a hydrogen atom,    -   (ii) a C₁₋₆ alkyl group optionally substituted by the same or        different 1 to 5 substituents selected from group B, or    -   (iii) a C₃₋₈ cycloalkyl group, or

R^(a) and R^(b) optionally form, together with the nitrogen atom bondedthereto, a saturated monocyclic hetero ring optionally containing,besides carbon atom and one nitrogen atom, 1 to 5 hetero atoms selectedfrom a nitrogen atom, an oxygen atom and a sulfur atom, and optionallysubstituted by the same or different 1 to 5 substituents selected fromgroup B, or

-   (3) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group A, wherein R²¹,    R³¹, R⁴¹ and R⁵¹ are not hydrogen atoms at the same time,-   R⁶¹ is a halogen atom, and-   R⁶² is a hydrogen atom or a halogen atom.-   [14] The compound of the above-mentioned [13], wherein R²¹ is a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from group A, and-   R³¹, R⁴¹ and R⁵¹ are each a hydrogen atom, or a pharmaceutically    acceptable salt thereof, or a solvate thereof.-   [15] The compound of the above-mentioned [13], wherein R²¹ is a C₁₋₆    alkyl group, and-   R³¹, R⁴¹ and R⁵¹ are each a hydrogen atom,-   or a pharmaceutically acceptable salt thereof, or a solvate thereof.-   [16] The compound of the above-mentioned [13], wherein R⁴¹ is a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from group A, and-   R²¹, R³¹ and R⁵¹ are each a hydrogen atom,-   or a pharmaceutically acceptable salt thereof, or a solvate thereof.-   [17] The compound of the above-mentioned [13], wherein R²¹ is a C₁₋₆    alkyl group optionally substituted by the same or different 1 to 5    substituents selected from group A,-   R⁴¹ is a C₁₋₆ alkyl group, and-   R³¹ and R⁵¹ are each a hydrogen atom,-   or a pharmaceutically acceptable salt thereof, or a solvate thereof.-   [18] The compound of the above-mentioned [1], which is represented    by the following formula [I-2], or a pharmaceutically acceptable    salt thereof, or a solvate thereof:

wherein

-   R¹² is a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from    -   (i) a C₃₋₈ cycloalkyl group, and    -   (ii) a C₁₋₆ alkoxy group,-   R²², R³², R⁴² and R⁵² are the same or different and each is-   (1) a hydrogen atom,-   (2) —CO—NR^(a)R^(b)

wherein R^(a) and R^(b) are the same or different and each is

-   -   (i) a hydrogen atom,    -   (ii) a C₁₋₆ alkyl group optionally substituted by the same or        different 1 to 5 substituents selected from group B, or    -   (iii) a C₃₋₈ cycloalkyl group, or

R^(a) and R^(b) optionally form, together with the nitrogen atom bondedthereto, a saturated monocyclic hetero ring optionally containing,besides carbon atom and one nitrogen atom, 1 to 5 hetero atoms selectedfrom a nitrogen atom, an oxygen atom and a sulfur atom, and optionallysubstituted by the same or different 1 to 5 substituents selected fromgroup B, or

-   (3) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from group A, wherein R²²,    R³², R⁴² and R⁵² are not hydrogen atoms at the same time,-   R⁶³ is a halogen atom, and-   R⁶⁴ is a hydrogen atom or a halogen atom.-   [19] The compound of the above-mentioned [18], wherein R⁴² is    —CO—NR^(a)R^(b)

wherein R^(a) and R^(b) form, together with the nitrogen atom bondedthereto, a saturated monocyclic hetero ring optionally containing,besides carbon atom and one nitrogen atom, 1 to 5 hetero atoms selectedfrom a nitrogen atom, an oxygen atom and a sulfur atom, and optionallysubstituted by the same or different 1 to 5 substituents selected fromgroup B,

-   R⁵² is a C₁₋₆ alkyl group, and-   R²² and R³² is a hydrogen atom,-   or a pharmaceutically acceptable salt thereof, or a solvate thereof.-   [20] The compound of the above-mentioned [1], which is represented    by the formula, or a pharmaceutically acceptable salt thereof, or a    solvate thereof:

-   [21] The compound of the above-mentioned [1], which is represented    by the formula, or a pharmaceutically acceptable salt thereof, or a    solvate thereof:

-   [22] The compound of the above-mentioned [1], which is represented    by the formula, or a pharmaceutically acceptable salt thereof, or a    solvate thereof:

-   [23] The compound of the above-mentioned [1], which is represented    by the formula, or a pharmaceutically acceptable salt thereof, or a    solvate thereof:

-   [24] The compound of the above-mentioned [1], which is represented    by the formula, or a pharmaceutically acceptable salt thereof, or a    solvate thereof:

-   [25] The compound of the above-mentioned [1], which is represented    by the formula, or a pharmaceutically acceptable salt thereof, or a    solvate thereof:

-   [26] The compound of the above-mentioned [1], which is represented    by the formula, or a pharmaceutically acceptable salt thereof, or a    solvate thereof:

-   [27] The compound of the above-mentioned [1], which is represented    by the formula, or a pharmaceutically acceptable salt thereof, or a    solvate thereof:

-   [28] The compound of the above-mentioned [1], which is represented    by the formula, or a pharmaceutically acceptable salt thereof, or a    solvate thereof:

-   [29] The compound of the above-mentioned [1], which is represented    by the formula, or a pharmaceutically acceptable salt thereof, or a    solvate thereof:

-   [30] A pharmaceutical composition comprising the compound of any one    of the above-mentioned [1] to [29] or a pharmaceutically acceptable    salt thereof, or a solvate thereof, and a pharmaceutically    acceptable carrier.-   [31] An anti-HIV agent comprising the compound of any one of the    above-mentioned [1] to [29] or a pharmaceutically acceptable salt    thereof, or a solvate thereof, as an active ingredient.-   [32] An HIV integrase inhibitor comprising the compound of any one    of the above-mentioned [1] to [29] or a pharmaceutically acceptable    salt thereof, or a solvate thereof, as an active ingredient.-   [33] An anti-HIV agent comprising the compound of any one of the    above-mentioned [1] to [29] or a pharmaceutically acceptable salt    thereof, or a solvate thereof, in combination with one or more other    kinds of anti-HIV active substances.-   [34] Use of the compound of any one of the above-mentioned [1] to    [29] or a pharmaceutically acceptable salt thereof, or a solvate    thereof, for the production of an anti-HIV agent.-   [35] Use of the compound of any one of the above-mentioned [1] to    [29] or a pharmaceutically acceptable salt thereof, or a solvate    thereof, for the production of an HIV integrase inhibitor.-   [36] A method for the prophylaxis or treatment of an HIV infectious    disease in a mammal, which comprises administering an effective    amount of the compound of any one of the above-mentioned [1] to [29]    or a pharmaceutically acceptable salt thereof, or a solvate thereof,    to said mammal.-   [37] The method of the above-mentioned [36], which further comprises    administering an effective amount of one or more other kinds of    anti-HIV active substances to the mammal.-   [38] A method for inhibiting HIV integrase in a mammal, which    comprises administering an effective amount of the compound of any    one of the above-mentioned [1] to [29] or a pharmaceutically    acceptable salt thereof, or a solvate thereof, to said mammal.-   [39] An anti-HIV composition comprising the compound of any one of    the above-mentioned [1] to [29] or a pharmaceutically acceptable    salt thereof, or a solvate thereof, and a pharmaceutically    acceptable carrier.-   [40] A pharmaceutical composition for inhibiting HIV integrase,    comprising the compound of any one of the above-mentioned [1] to    [29] or a pharmaceutically acceptable salt thereof, or a solvate    thereof, and a pharmaceutically acceptable carrier.-   [41] A commercial package comprising the pharmaceutical composition    of the above-mentioned [30] and a written matter associated    therewith, which states that the pharmaceutical composition can or    should be used for treating HIV.-   [42] A kit comprising the pharmaceutical composition of the    above-mentioned [30] and a written matter associated therewith,    which states that the pharmaceutical composition can or should be    used for treating HIV.

Effect of the Invention

The compound of the present invention can be medicaments effective forthe prophylaxis or treatment of HIV infections or AIDS, as anti-HIVagents, having an HIV integrase inhibitory activity. In addition, by acombined use with other anti-HIV agent(s) such as protease inhibitor,reverse transcriptase inhibitor and the like, they can be more effectiveanti-HIV agents. Furthermore, having high inhibitory activity specificfor integrase, they can be medicaments safe for human body with a fewerside effects.

DESCRIPTION OF EMBODIMENTS

The definitions of respective substituents and respective moieties usedin the present specification are as follows.

The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atomor an iodine atom.

The “C₁₋₆ alkyl group” is a straight chain or branched chain alkyl grouphaving 1 to 6 carbon atoms, preferably a straight chain or branchedchain alkyl group having 1 to 4 carbon atoms. Specific examples includea methyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, apentyl group, an isopentyl group, a 1,1-dimethylpropyl group, a1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropylgroup, a hexyl group and the like.

The “C₁₋₆ alkoxy group” is a straight chain or branched chain alkoxygroup having 1 to 6 carbon atoms, preferably a straight chain orbranched chain alkoxy group having 1 to 4 carbon atoms. Specificexamples include a methoxy group, an ethoxy group, a propoxy group, anisopropyloxy group, a butoxy group, an isobutyloxy group, atert-butyloxy group, a pentyloxy group, a hexyloxy group and the like.

The “C₁₋₆ alkoxy-C₁₋₆ alkyl group” is that wherein the alkoxy moiety isthe “C₁₋₆ alkoxy group” defined above, and the alkyl moiety is the “C₁₋₆alkyl group” defined above. Preferred is a C₁₋₆ alkoxy-C₁₋₆ alkyl groupwherein the alkoxy moiety is a straight chain or branched chain alkoxygroup having 1 to 4 carbon atoms, and the alkyl moiety is a straightchain or branched chain alkyl group having 1 to 4 carbon atoms. Examplesof the C₁₋₆ alkoxy-C₁₋₆ alkyl group include a methoxymethyl group, amethoxyethyl group, a methoxypropyl group, a methoxybutyl group, amethoxypentyl group, a methoxyhexyl group, an ethoxymethyl group, anethoxyethyl group, an ethoxypropyl group, an ethoxybutyl group, anethoxypentyl group, an ethoxyhexyl group, a propoxymethyl group, apropoxyethyl group, a propoxypropyl group, a propoxybutyl group, apropoxypentyl group, a propoxyhexyl group, a butoxymethyl group, abutoxyethyl group, a butoxypropyl group, a butoxybutyl group, abutoxypentyl group, a butoxyhexyl group, a pentyloxymethyl group, apentyloxyethyl group, a pentyloxypropyl group, a pentyloxybutyl group, apentyloxypentyl group, a pentyloxyhexyl group, a hexyloxymethyl group, ahexyloxyethyl group, a hexyloxypropyl group, a hexyloxybutyl group, ahexyloxypentyl group, a hexyloxyhexyl group and the like.

The “C₁₋₆ alkoxy-C₁₋₆ alkoxy group” is that wherein the C₁₋₆ alkoxymoiety is the “C₁₋₆ alkoxy group” defined above, preferably a straightchain or branched chain alkoxy group having 1 to 4 carbon atoms.Examples thereof include a methoxymethoxy group, a methoxyethoxy group,a methoxypropoxy group, a methoxybutoxy group, a methoxypentyloxy group,a methoxyhexyloxy group, an ethoxymethoxy group, an ethoxyethoxy group,an ethoxypropoxy group, an ethoxybutoxy group, an ethoxypentyloxy group,an ethoxyhexyloxy group, a propoxymethoxy group, a propoxyethoxy group,a propoxypropoxy group, a propoxybutoxy group, a propoxypentyloxy group,a propoxyhexyloxy group, a butoxymethoxy group, a butoxyethoxy group, abutoxypropoxy group, a butoxybutoxy group, a butoxypentyloxy group, abutoxyhexyloxy group, a pentyloxymethoxy group, a pentyloxyethoxy group,a pentyloxypropoxy group, a pentyloxybutoxy group, a pentyloxypentyloxygroup, a pentyloxyhexyloxy group, a hexyloxymethoxy group, ahexyloxyethoxy group, a hexyloxypropoxy group, a hexyloxybutoxy group, ahexyloxypentyloxy group, a hexyloxyhexyloxy group and the like.

The “C₁₋₆ alkyl-carbonyl group” is an alkyl-carbonyl group wherein theC₁₋₆ alkyl moiety is the “C₁₋₆ alkyl group” defined above, preferably astraight chain or branched chain alkyl group having 1 to 4 carbon atoms.Examples thereof include a methylcarbonyl group, an ethylcarbonyl group,a propylcarbonyl group, an isopropylcarbonyl group, a butylcarbonylgroup, an isobutylcarbonyl group, a sec-butylcarbonyl group, atert-butylcarbonyl group, a pentylcarbonyl group, an isopentylcarbonylgroup, a 1,1-dimethylpropylcarbonyl group, hexylcarbonyl group and thelike.

The “C₁₋₆ alkyl-sulfonyl group” is an alkyl-sulfonyl group wherein theC₁₋₆ alkyl moiety is the “C₁₋₆ alkyl group” defined above, preferably astraight chain or branched chain alkyl group having 1 to 4 carbon atoms.Examples thereof include a methylsulfonyl group, an ethylsulfonyl group,a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonylgroup, an isobutylsulfonyl group, a sec-butylsulfonyl group, atert-butylsulfonyl group, a pentylsulfonyl group, an isopentylsulfonylgroup, a 1,1-dimethylpropylsulfonyl group, a hexylsulfonyl group and thelike.

The “C₃₋₈ cycloalkyl group” is a saturated cycloalkyl group having 3 to8 carbon atoms, preferably 3 to 5 carbon atoms, and examples thereofinclude a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, acyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like.

The “C₃₋₈ cycloalkane” is saturated cycloalkane having 3 to 8 carbonatoms, preferably 3 to 5 carbon atoms, and examples thereof includecyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,cyclooctane and the like.

The “hetero ring” means a saturated or unsaturated (including partiallyunsaturated and completely unsaturated) monocyclic hetero ringcontaining, besides carbon atom, 1 to 6 hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom, or a fused ring of thehetero rings, or a fused ring of a carbon ring selected from benzene,cyclopentane and cyclohexane, and the hetero ring.

Examples of the above-mentioned “saturated monocyclic hetero ringcontaining, besides carbon atom, 1 to 6 hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom” include a 4- to7-membered saturated monocyclic hetero ring containing, besides carbonatom, 1 to 6 hetero atoms selected from a nitrogen atom, an oxygen atomand a sulfur atom, and the like. Specific examples thereof includeazetidine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,imidazolidine, pyrazolidine, 1,3-dioxolane, 1,3-oxathioran, oxazolidine,thiazolidine, piperidine, piperazine, tetrahydropyran,tetrahydrothiopyran, dioxane, morpholine, thiomorpholine and the like.

Examples of the above-mentioned “unsaturated (including partiallyunsaturated and completely unsaturated) monocyclic hetero ringcontaining, besides carbon atom, 1 to 6 hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom” include a 4- to7-membered unsaturated (including partially unsaturated and completelyunsaturated) monocyclic hetero ring containing, besides carbon atom, 1to 6 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, and the like. Specific examples thereof include pyrroline,furan, thiophene, imidazole, imidazoline, pyrazole, oxazole, isoxazole,thiazole, isothiazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole,1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole,1,2,4-thiadiazole, furazan, pyridine, pyrimidine, 3,4-dihydropyrimidine,pyridazine, pyrazine, 1,3,5-triazine, pyrazoline, oxazoline,isooxazoline, thiazoline, isothiazoline, pyran and the like.

Examples of the above-mentioned “fused ring of the hetero rings, orfused ring of a carbon ring selected from benzene, cyclopentane andcyclohexane, and the hetero ring” include indole, isoindole,benzimidazole, indazole, benzothiazole, benzofuran, isobenzofuran,indolizine, quinoline, isoquinoline, 1,2-dihydroquinoline, quinazoline,quinoxaline, cinnoline, phthalazine, quinolizidine, purine, pteridine,indoline, isoindoline, 5,6,7,8-tetrahydroquinoline,1,2,3,4-tetrahydroquinoline, 1,3-benzodioxolane,3,4-methylenedioxypyridine, 4,5-ethylenedioxypyrimidine, chromene,chromane, isochromane, 1,2,4-benzotriazine and the like.

The “saturated monocyclic hetero ring” formed by R^(a) and R^(b)together with the nitrogen atom bonded thereto means a saturatedmonocyclic hetero ring optionally containing, besides carbon atom andone nitrogen atom, 1 to 5 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom, and examples thereof include a 4- to7-membered (e.g., 4- to 6-membered) saturated monocyclic hetero ringoptionally containing, besides carbon atom and one nitrogen atom, 1 to 5(e.g., 1 to 3, preferably 1) hetero atoms selected from nitrogen atom,oxygen atom and sulfur atom, and the like. Specific examples of thesaturated monocyclic hetero ring include those exemplified as theabove-mentioned “saturated monocyclic hetero ring containing, besidecarbon atom, 1 to 6 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom”, which contain, beside carbon atom andone nitrogen atom, 1 to 5 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom.

The saturated monocyclic hetero ring is optionally substituted by thesame or different 1 to 5 (e.g., 1 to 3, preferably 1) substituentsselected from the following group B.

The “saturated monocyclic hetero ring” formed by R² and R³ or R⁴ and R⁵,together with the carbon atom bonded thereto means a saturatedmonocyclic hetero ring containing, besides carbon atom, 1 to 6 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,and examples thereof include a 5- to 7-membered (e.g., 6-membered)saturated monocyclic hetero ring containing, besides carbon atom, 1 to 6(e.g., 1 to 3, preferably 1) hetero atoms selected from a nitrogen atom,an oxygen atom and a sulfur atom, and the like. Specific examples of thesaturated monocyclic hetero ring include those similar to the saturatedmonocyclic hetero rings exemplified as the above-mentioned “saturatedmonocyclic hetero ring containing, besides carbon atom, 1 to 6 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom”.

The “saturated monocyclic hetero ring” formed by R^(A1) and R^(A2)together with the nitrogen atom bonded thereto means a saturatedmonocyclic hetero ring optionally containing, besides carbon atom andone nitrogen atom, 1 to 3 hetero atoms selected from a nitrogen atom, anoxygen atom and a sulfur atom, and examples thereof include a 4- to6-membered saturated monocyclic hetero ring optionally containing,besides carbon atom and one nitrogen atom, 1 to 3 (e.g., 1) hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom and thelike. Specific examples of the saturated monocyclic hetero ring includethose exemplified as the above-mentioned “saturated monocyclic heteroring containing, besides carbon atom, 1 to 6 hetero atoms selected froma nitrogen atom, an oxygen atom and a sulfur atom”, which optionallycontain, besides carbon atom and one nitrogen atom, 1 to 3 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom.

The saturated monocyclic hetero ring is optionally substituted by thesame or different 1 to 5 substituents selected from the following groupB.

The “hetero ring” formed by R^(A3) and R^(A4) together with the nitrogenatom bonded thereto means a hetero ring optionally containing, besidescarbon atom and one nitrogen atom, 1 to 5 hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom, and examples thereofinclude a 4- to 6-membered (e.g., 5-membered) monocyclic hetero ring, a8- to 10-membered (e.g., 9-membered) fused cyclic hetero ring and thelike, optionally containing, besides carbon atom and one nitrogen atom,1 to 5 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom. Specific examples of the hetero ring include thoseexemplified as the above-mentioned “hetero ring”, which optionallycontain, besides carbon atom and one nitrogen atom, 1 to 5 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom.

The hetero ring is optionally substituted by 1 or 2 oxo groups.

The “saturated monocyclic heterocyclic group” for R¹ means a saturatedmonocyclic heterocyclic group containing, besides carbon atom, 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom, and examples thereof include a 5- or 6-membered saturatedmonocyclic heterocyclic group containing, besides carbon atom, 1 to 3(e.g., 1) hetero atoms selected from a nitrogen atom, an oxygen atom anda sulfur atom, and the like. Specific examples of the saturatedmonocyclic heterocyclic group include groups derived from thoseexemplified as the above-mentioned “saturated monocyclic hetero ringcontaining, besides carbon atom, 1 to 6 hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom”, which optionallycontain, besides carbon atom, 1 to 3 hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom and the like. Examplesthereof include a pyrrolidinyl group, a tetrahydrofuryl (e.g.,3-tetrahydrofuryl) group, a tetrahydrothienyl group, an imidazolidinylgroup, a pyrazolidinyl group, a 1,3-dioxolanyl group, a 1,3-oxathioranylgroup, an oxazolidinyl group, a thiazolidinyl group, a piperidinylgroup, a piperazinyl group, a tetrahydropyranyl group, atetrahydrothiopyranyl group, a dioxanyl group, a morpholinyl group, athiomorpholinyl group and the like.

The “group A” includes the following substituents (a) to (i).

-   (a) —CO—NR^(A1)R^(A2)

wherein R^(A1) and R^(A2) are the same or different and each is

-   -   (i) a hydrogen atom,    -   (ii) a C₁₋₆ alkyl group optionally substituted by the same or        different 1 to 5 substituents selected from the following group        B, or    -   (iii) a C₃₋₈ cycloalkyl group, or

R^(A1) and R^(A2) optionally form, together with the nitrogen atombonded thereto, a saturated monocyclic hetero ring optionallycontaining, besides carbon atom and one nitrogen atom, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,and optionally substituted by the same or different 1 to 5 substituentsselected from the following group B,

-   (b) a hydroxyl group,-   (c) a C₁₋₆ alkoxy group,-   (d) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group,-   (e) a cyano group,-   (f) —NR^(A3)R^(A4)

wherein R^(A3) and R^(A4) are the same or different and each is

-   -   (i) a hydrogen atom,    -   (ii) a C₁₋₆ alkyl group,    -   (iii) a C₁₋₆ alkyl-carbonyl group, or    -   (iv) a C₁₋₆ alkyl-sulfonyl group, or

R^(A3) and R^(A4) optionally form, together with the nitrogen atombonded thereto, a hetero ring optionally containing, besides carbon atomand one nitrogen atom, 1 to 5 hetero atoms selected from a nitrogenatom, an oxygen atom and a sulfur atom, and optionally substituted by 1or 2 oxo groups,

-   (g) a carboxyl group,-   (h) a C₁₋₆ alkyl-sulfonyl group, and-   (i) a C₁₋₆ alkyl-carbonyl group.

The “C₁₋₆ alkyl group optionally substituted by the same or different 1to 5 substituents selected from group A” is that wherein the “C₁₋₆ alkylgroup” defined above is optionally substituted by the same or different1 to 5 (e.g., 1 to 3, preferably 1) substituents selected from “group A”defined above, and includes an unsubstituted C₁₋₆ alkyl group.

The “group B” includes the following substituents (a) to (e).

-   (a) a hydroxyl group,-   (b) a C₁₋₆ alkoxy group,-   (c) a C₁₋₆ alkoxy-C₁₋₆ alkyl group,-   (d) a C₃₋₈ cycloalkyl group, and-   (e) an oxo group.

The “C₁₋₆ alkyl group optionally substituted by the same or different 1to 5 substituents selected from group B” is that wherein the “C₁₋₆ alkylgroup” defined above is optionally substituted by the same or different1 to 5 (e.g., 1 to 3, preferably 1) substituents selected from the“group B” defined above, and includes an unsubstituted C₁₋₆ alkyl group.

The “saturated monocyclic hetero ring is optionally substituted by thesame or different 1 to 5 substituents selected from group B” for R^(a)and R^(b), or R^(A1) and R^(A2) means that the “saturated monocyclichetero ring” defined above which is formed by R^(a) and R^(b), or R^(A1)and R^(A2) together with the nitrogen atom bonded thereto is optionallysubstituted by the same or different 1 to 5 (e.g., 1 to 3, preferably 1)substituents selected from the “group B” defined above, and includes anunsubstituted saturated monocyclic hetero ring.

In the above-mentioned formula [I], preferable groups are as describedbelow.

R¹ is

-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from    -   (i) a C₃₋₈ cycloalkyl group, and    -   (ii) a C₁₋₆ alkoxy group,-   (2) a C₃₋₈ cycloalkyl group, or-   (3) a saturated monocyclic heterocyclic group containing, besides    carbon atom, 1 to 3 hetero atoms selected from a nitrogen atom, an    oxygen atom and a sulfur atom.

Preferable embodiment of R¹ is a C₁₋₆ alkyl group optionally substitutedby the same or different 1 to 5 substituents selected from

-   -   (i) a C₃₋₈ cycloalkyl group, and    -   (ii) a C₁₋₆ alkoxy group.

More preferable embodiment of R¹ is a C₁₋₆ alkyl group.

A different, more preferable embodiment of R¹ is a C₁₋₆ alkyl groupsubstituted by a C₃₋₈ cycloalkyl group.

A different, preferable embodiment of R¹ is a C₃₋₈ cycloalkyl group.

Further different preferable embodiments of R¹ are (1) a C₁₋₆ alkylgroup optionally substituted by the same or different 1 to 3 C₃₋₈cycloalkyl groups,

-   (2) a C₃₋₈ cycloalkyl group,-   (3) a 5- or 6-membered saturated monocyclic heterocyclic group    containing, besides carbon atom, 1 to 3 (e.g., 1) hetero atoms    selected from a nitrogen atom, an oxygen atom and a sulfur atom, and    the like.

Of these, preferred are a methyl group, a cyclopropylmethyl group, anethyl group, a 1-cyclopropylethyl group, a propyl group, an isopropylgroup, a butyl group, an isobutyl group, a sec-butyl group, a tert-butylgroup, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a1-ethylpropyl group, a cyclopropyl group, a cyclobutyl group, acyclopentyl group, a tetrahydrofuryl (e.g., 3-tetrahydrofuryl) group andthe like.

R², R³, R⁴ and R⁵ are the same or different and each is

-   (1) a hydrogen atom,-   (2) a carboxyl group,-   (3) —CO—NR^(a)R^(b)

wherein R^(a) and R^(b) are the same or different and each is

-   -   (i) a hydrogen atom,    -   (ii) a C₁₋₆ alkyl group optionally substituted by the same or        different 1 to 5 substituents selected from the above-mentioned        group B, or    -   (iii) a C₃₋₈ cycloalkyl group, or

R^(a) and R^(b) optionally form, together with the nitrogen atom bondedthereto, a saturated monocyclic hetero ring optionally containing,besides carbon atom and one nitrogen atom, 1 to 5 hetero atoms selectedfrom a nitrogen atom, an oxygen atom and a sulfur atom, and optionallysubstituted by the same or different 1 to 5 substituents selected fromthe above-mentioned group B,

-   (4) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the above-mentioned    group A, or-   (5) a cyano group.

In a preferable embodiment of R², R³, R⁴ and R⁵, one of R², R³, R⁴ andR⁵ is —CO—NR^(a)R^(b)

wherein R^(a) and R^(b) are the same or different and each is

-   -   (i) a hydrogen atom,    -   (ii) a C₁₋₆ alkyl group optionally substituted by the same or        different 1 to 5 substituents selected from the above-mentioned        group B, or    -   (iii) a C₃₋₈ cycloalkyl group, or

R^(a) and R^(b) optionally form, together with the nitrogen atom bondedthereto, a saturated monocyclic hetero ring optionally containing,besides carbon atom and one nitrogen atom, 1 to 5 hetero atoms selectedfrom a nitrogen atom, an oxygen atom and a sulfur atom, and optionallysubstituted by the same or different 1 to 5 substituents selected fromthe above-mentioned group B.

In another preferable embodiment of R², R³, R⁴ and R⁵, one of R², R³, R⁴and R⁵ is a C₁₋₆ alkyl group optionally substituted by the same ordifferent 1 to 5 substituents selected from the above-mentioned group A.

Further preferable embodiments of R², R³, R⁴ and R⁵ are respectivelyshown below.

As R², preferred are

-   (1) a hydrogen atom,-   (2) a carboxyl group,-   (3) —CO—NR^(a)R^(b)

wherein R^(a) and R^(b) are the same or different and each is

-   -   (i) a hydrogen atom, and    -   (ii) a C₁₋₆ alkyl group, or    -   R^(a) and R^(b) optionally form, together with the nitrogen atom        bonded thereto, a 4- to 7-membered (e.g., 4- to 6-membered)        saturated monocyclic hetero ring optionally containing, besides        carbon atom and one nitrogen atom, 1 to 5 (e.g., 1 to 3,        preferably 1) hetero atoms selected from a nitrogen atom, an        oxygen atom and a sulfur atom,

-   (4) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 3 (e.g., 1) substituents selected from    -   (a) —CO—NR^(A1)R^(A2)        -   wherein R^(A1) and R^(A2) are the same or different and each            is            -   (i) a hydrogen atom, or            -   (ii) a C₁₋₆ alkyl group,    -   (b) a hydroxyl group,    -   (c) a C₁₋₆ alkoxy group,    -   (d) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group,    -   (e) a cyano group,    -   (f) —NR^(A3)R^(A4)        -   wherein R^(A3) and R^(A4) are the same or different and each            is            -   (i) a hydrogen atom,            -   (ii) a C₁₋₆ alkyl group,            -   (iii) a C₁₋₆ alkyl-carbonyl group, or            -   (iv) a C₁₋₆ alkyl-sulfonyl group, and    -   (g) a carboxyl group, and

-   (5) a cyano group.

As R², more preferred are

-   (1) a hydrogen atom,-   (2) a carboxyl group,-   (3) —CO—NR^(a)R^(b)    -   wherein R^(a) and R^(b) are the same or different and each is        -   (i) a hydrogen atom,        -   (ii) a methyl group,        -   (ii′) an ethyl group,        -   (ii″) an isopropyl group, or        -   (ii′″) a tert-butyl group, or    -   R^(a) and R^(b) optionally form, together with the nitrogen atom        bonded thereto, a saturated monocyclic hetero ring selected from        azetidine, pyrrolidine and morpholine,-   (4) a methyl group, an ethyl group, a propyl group, or an isopropyl    group, which is optionally substituted by the same or different 1 to    3 (e.g., 1) substituents selected from    -   (a) —CO—NR^(A1)R^(A2)        -   wherein R^(A1) and R^(A2) are the same or different and each            is            -   (i) a hydrogen atom, or            -   (ii) a methyl group,    -   (b) a hydroxyl group,    -   (c) a methoxy group,    -   (c′) an ethoxy group,    -   (c″) an isopropoxy group,    -   (d) a methoxyethoxy group,    -   (e) a cyano group,    -   (f) —NR^(A3)R^(A4)        -   wherein R^(A3) and R^(A4) are the same or different and each            is a hydrogen atom, a methyl group, a methylcarbonyl group,            an isopropylcarbonyl group, a tert-butylcarbonyl group, a            1,1-dimethylpropylcarbonyl group or a methylsulfonyl group,            and    -   (g) a carboxyl group, and-   (5) a cyano group.

As R³, preferred are

-   (1) a hydrogen atom, and-   (2) a C₁₋₆ alkyl group optionally substituted by a C₁₋₆ alkoxy    group.

As R³, more preferred are a hydrogen atom, a methyl group and amethoxymethyl group.

As R⁴, preferred are

-   (1) a hydrogen atom,-   (2) a carboxyl group,-   (3) —CO—NR^(a)R^(b)    -   wherein R^(a) and R^(b) are the same or different and each is        -   (i) a hydrogen atom,        -   (ii) a C₁₋₆ alkyl group optionally substituted by the same            or different 1 to 5 (e.g., 1 to 3, preferably 1)            substituents selected from a C₁₋₆ alkoxy group and a C₃₋₈            cycloalkyl group, or        -   (iii) a C₃₋₈ cycloalkyl group, or    -   R^(a) and R^(b) optionally form, together with the nitrogen atom        bonded thereto, a saturated monocyclic hetero ring which is a 4-        to 7-membered (e.g., 4- to 6-membered) saturated monocyclic        hetero ring which is optionally containing, besides carbon atom        and one nitrogen atom, 1 to 5 (e.g., 1 to 3, preferably 1)        hetero atoms selected from a nitrogen atom, an oxygen atom and a        sulfur atom, and optionally substituted by the same or different        1 to 5 (e.g., 1 to 3, preferably 1) substituents selected        from (a) a hydroxyl group, (b) a C₁₋₆ alkoxy group, (c) a C₁₋₆        alkoxy-C₁₋₆ alkyl group and (d) an oxo group,-   (4) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 (e.g., 1 to 3, preferably 1) substituents    -   (a) —CO—NR^(A1)R^(A2)        -   wherein R^(A1) and R^(A2) are the same or different and each            is selected from            -   (i) a hydrogen atom,            -   (ii) a C₁₋₆ alkyl group optionally substituted by the                same or different 1 to 5 (e.g., 1 to 3, preferably 1)                C₁₋₆ alkoxy groups, or            -   (iii) a C₃₋₈ cycloalkyl group, or        -   R^(A1) and R^(A2) optionally form, together with the            nitrogen atom bonded thereto, a saturated monocyclic hetero            ring which is a 4- to 6-membered saturated monocyclic hetero            ring optionally containing, besides carbon atom and one            nitrogen atom, 1 to 3 (e.g., 1) hetero atoms selected from a            nitrogen atom, an oxygen atom and a sulfur atom, and            optionally substituted by a C₁₋₆ alkoxy group,    -   (b) a hydroxyl group,    -   (c) a C₁₋₆ alkoxy group,    -   (d) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group,    -   (e) a cyano group,    -   (f) —NR^(A3)R^(A4)        -   wherein R^(A3) and R^(A4) are the same or different and each            is            -   (i) a hydrogen atom,            -   (ii) a C₁₋₆ alkyl group,            -   (iii) a C₁₋₆ alkyl-carbonyl group, or            -   (iv) a C₁₋₆ alkyl-sulfonyl group, or        -   R^(A3) and R^(A4) optionally form, together with the            nitrogen atom bonded thereto, a hetero ring which is a 4- to            7-membered (e.g., 6-membered) monocyclic hetero ring, or a            8- to 10-membered (e.g., 9-membered) fused cyclic hetero            ring optionally containing, besides carbon atom and one            nitrogen atom, 1 to 5 hetero atoms selected from a nitrogen            atom, an oxygen atom and a sulfur atom, and optionally            substituted by 1 or 2 oxo groups,    -   (g) a carboxyl group,    -   (h) a C₁₋₆ alkyl-sulfonyl group, and    -   (i) a C₁₋₆ alkyl-carbonyl group, and-   (5) a cyano group.

As R⁴, more preferred are

-   (1) a hydrogen atom,-   (2) a carboxyl group,-   (3) —CO—NR^(a)R^(b)    -   wherein R^(a) and R^(b) are the same or different and each is        -   (i) a hydrogen atom,        -   (ii) a methyl group, an ethyl group, an isopropyl group or            an isobutyl group, which is optionally substituted by the            same or different one substituent selected from a methoxy            group and a cyclopropyl group, or        -   (iii) a cyclopropyl group, or    -   R^(a) and R^(b) optionally form, together with the nitrogen atom        bonded thereto, a saturated monocyclic hetero ring selected from        azetidine, pyrrolidine, piperidine and morpholine, which is        optionally substituted by one substituent selected from a        hydroxyl group, a methoxy group, a methoxymethyl group and an        oxo group,-   (4) a methyl group, an ethyl group, a propyl group, an isopropyl    group or a tert-butyl group, which is optionally substituted by one    or two substituents selected from    -   (a) —CO—NR^(A1)R^(A2)        -   wherein R^(A1) and R^(A2) are the same or different and each            is            -   (i) a hydrogen atom,            -   (ii) a methyl group, an ethyl group, an isopropyl group                or an isobutyl group, which is optionally substituted by                a methoxy group, or            -   (iii) a cyclopropyl group, or        -   R^(A1) and R^(A2) optionally form, together with the            nitrogen atom bonded thereto, a saturated monocyclic hetero            ring selected from azetidine, piperidine and morpholine, and            optionally substituted by a methoxy group,    -   (b) a hydroxyl group,    -   (c) a methoxy group,    -   (c′) an ethoxy group,    -   (c″) a propoxy group,    -   (c′″) an isopropoxy group,    -   (c″″) a butoxy group,    -   (d) a methoxyethoxy group,    -   (d′) an ethoxyethoxy group,    -   (d″) a methoxypropoxy group,    -   (d′″) a methoxyisopropoxy group,    -   (d″″) an isopropoxyethoxy group,    -   (e) a cyano group,    -   (f) —NR^(A3)R^(A4)        -   wherein R^(A3) and R^(A4) are the same or different and each            is a hydrogen atom, a methyl group, an ethyl group, an            isopropyl group, a methylcarbonyl group, an ethylcarbonyl            group, an isopropylcarbonyl group, a methylsulfonyl group or            a tert-butylsulfonyl group, or        -   R^(A3) and R^(A4) optionally form, together with the            nitrogen atom bonded thereto, pyrazole, triazole (e.g.,            1,2,4-triazole), tetrazole, oxazolidine or isoindoline,            which is optionally substituted by 1 or 2 oxo groups,    -   (g) a carboxyl group,    -   (h) a methylsulfonyl group, and    -   (i) a methylcarbonyl group, and-   (5) a cyano group.

As R⁵, preferred are a hydrogen atom and a C₁₋₆ alkyl group optionallysubstituted by one substituent selected from a C₁₋₆ alkoxy group and aC₁₋₆ alkoxy-C₁₋₆ alkoxy group.

As R⁵, more preferred are a hydrogen atom and a methyl group or an ethylgroup, which is optionally substituted by one substituent selected froma methoxy group and a methoxyethoxy group.

R² and R³, or R⁴ and R⁵ optionally form, together with the carbon atombonded thereto, i) C₃₋₈ cycloalkane or ii) a saturated monocyclic heteroring containing, besides carbon atom, 1 to 6 hetero atoms selected froma nitrogen atom, an oxygen atom and a sulfur atom.

As the ring formed by R² and R³, or R⁴ and R⁵ together with the carbonatom bonded thereto, preferred are

-   i) C₃₋₈ cycloalkane, and-   ii) a 5- to 7-membered (e.g., 6-membered) saturated monocyclic    hetero ring containing, besides carbon atom, 1 to 6 (e.g., 1 to 3,    preferably 1) hetero atoms selected from a nitrogen atom, an oxygen    atom and a sulfur atom.

As the ring formed by R² and R³, or R⁴ and R⁵ together with the carbonatom bonded thereto, more preferred are cyclopropane andtetrahydropyran.

Here, R², R³, R⁴ and R⁵ are not hydrogen atoms at the same time.

R⁶ is

-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 (e.g., 1 to 3) halogen atoms,-   (2) a C₁₋₆ alkoxy group,-   (3) a halogen atom, or-   (4) a C₃₋₈ cycloalkyl group.

As R⁶, preferred is a halogen atom.

Other preferable embodiments of R⁶ are a methyl group, a trifluoromethylgroup, a methoxy group, an ethoxy group, a fluorine atom, a chlorineatom, a bromine atom and a cyclopropyl group.

Y is

-   (1) CH, or-   (2) a nitrogen atom.

As Y, preferred is CH.

Other preferable embodiment of Y is a nitrogen atom.

m is an integer of 1 to 5, and when m is an integer of 2 to 5, theabove-mentioned R⁶ may be the same or different.

As m, preferred is 1 to 3.

As m, more preferred is 1 or 2.

n is an integer of 1 to 3.

As n, preferred is 1.

In the above-mentioned formula [I-1], preferable groups are as describedbelow.

R¹¹ is

-   (1) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from    -   (i) a C₃₋₈ cycloalkyl group, and    -   (ii) a C₁₋₆ alkoxy group, or-   (2) a C₃₋₈ cycloalkyl group.

As R¹¹, those exemplified as the preferable embodiments of R¹ in theabove-mentioned formula (I), which are within the scope of R¹¹, arepreferable.

R²¹, R³¹, R⁴¹ and R⁵¹ are the same or different and each is

-   (1) a hydrogen atom,-   (2) —CO—NR^(a)R^(b)    -   wherein R^(a) and R^(b) are the same or different and each is        -   (i) a hydrogen atom,        -   (ii) a C₁₋₆ alkyl group optionally substituted by the same            or different 1 to 5 substituents selected from the            above-mentioned group B, and        -   (iii) a C₃₋₈ cycloalkyl group, or    -   R^(a) and R^(b) optionally form, together with the nitrogen atom        bonded thereto, a saturated monocyclic hetero ring optionally        containing, besides carbon atom and one nitrogen atom, 1 to 5        hetero atoms selected from a nitrogen atom, an oxygen atom and a        sulfur atom, and optionally substituted by the same or different        1 to 5 substituents selected from the above-mentioned group B,        or-   (3) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the above-mentioned    group A.

As R²¹, preferred is a hydrogen atom.

Other preferable embodiment of R²¹ is a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe above-mentioned group A. More preferred is a C₁₋₆ alkyl group.

Examples of yet other preferable embodiment of R²¹ include thoseexemplified as the preferable embodiments of R² in the above-mentionedformula (I), which are within the scope of R²¹.

As R³¹, preferred is a hydrogen atom.

Examples of other preferable embodiment of R³¹ include those exemplifiedas the preferable embodiments of R³ in the above-mentioned formula (I),which are within the scope of R³¹.

As R⁴¹, preferred is a hydrogen atom.

Other preferable embodiment of R⁴¹ is a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromthe above-mentioned group A. More preferred is a C₁₋₆ alkyl group.

Examples of yet other preferable embodiment of R⁴¹ include thoseexemplified as the preferable embodiments of R⁴ in the above-mentionedformula (I), those contained within the scope of R⁴¹.

As R⁵¹, preferred is a hydrogen atom.

Other preferable embodiments of R⁵¹ are those exemplified as thepreferable embodiments of R⁵ in the above-mentioned formula (I), whichare within the scope of R⁵¹.

Here, R²¹, R³¹, R⁴¹ and R⁵¹ are not hydrogen atoms at the same time.

R⁶¹ is a halogen atom.

As R⁶¹, preferred are a fluorine atom and a chlorine atom.

R⁶² is a hydrogen atom or a halogen atom.

As R⁶², preferred are a hydrogen atom, a fluorine atom and a bromineatom.

In the above-mentioned formula [I-2], preferable groups are as describedbelow.

R¹² is a C₁₋₆ alkyl group optionally substituted by the same ordifferent 1 to 5 substituents selected from

-   -   (i) a C₃₋₈ cycloalkyl group, and    -   (ii) a C₁₋₆ alkoxy group.

As R¹², those exemplified as the preferable embodiments of R¹ in theabove-mentioned formula (I), which are within the scope of R¹², arepreferable.

R²², R³², R⁴² and R⁵² are the same or different and each is

-   (1) a hydrogen atom,-   (2) —CO—NR^(a)R^(b)

wherein R^(a) and R^(b) are the same or different and each is

-   -   (i) a hydrogen atom,    -   (ii) a C₁₋₆ alkyl group optionally substituted by the same or        different 1 to 5 substituents selected from the above-mentioned        group B, or    -   (iii) a C₃₋₈ cycloalkyl group, or

R^(a) and R^(b) optionally form, together with the nitrogen atom bondedthereto, a saturated monocyclic hetero ring optionally containing,besides carbon atom and one nitrogen atom, 1 to 5 hetero atoms selectedfrom a nitrogen atom, an oxygen atom and a sulfur atom, and optionallysubstituted by the same or different 1 to 5 substituents selected fromthe above-mentioned group B, or

-   (3) a C₁₋₆ alkyl group optionally substituted by the same or    different 1 to 5 substituents selected from the above-mentioned    group A.

As R²², preferred is a hydrogen atom.

Other preferable embodiments of R²² are those exemplified as thepreferable embodiments of R² in the above-mentioned formula (I), whichare within the scope of R²².

As R³², preferred is a hydrogen atom.

Other preferable embodiments of R³² are those exemplified as thepreferable embodiments of R³ in the above-mentioned formula (I), whichare within the scope of R³².

As R⁴², preferred is —CO—NR^(a)R^(b)

-   -   wherein R^(a) and R^(b) form, together with the nitrogen atom        bonded thereto, a saturated monocyclic hetero ring optionally        containing, besides carbon atom and one nitrogen atom, 1 to 5        hetero atoms selected from a nitrogen atom, an oxygen atom and a        sulfur atom, and optionally substituted by the same or different        1 to 5 substituents selected from the above-mentioned group B.

Other preferable embodiments of R⁴² are those exemplified as thepreferable embodiments of R⁴ in the above-mentioned formula (I), whichare within the scope of R⁴².

As R⁵², preferred is a C₁₋₆ alkyl group.

Other preferable embodiments of R⁵² are those exemplified as thepreferable embodiments of R⁵ in the above-mentioned formula (I), whichare within the scope of R⁵².

Here, R²², R³², R⁴² and R⁵² are not hydrogen atoms at the same time.

R⁶³ is a halogen atom.

As R⁶³, preferred is a fluorine atom.

R⁶⁴ is a hydrogen atom or a halogen atom.

As R⁶⁴, preferred are a hydrogen atom and a fluorine atom.

As the compound of the present invention, compounds represented by theabove-mentioned formula [I], the formula [I-1] and the formula [I-2],and compounds described in the following Examples are preferable.

A pharmaceutically acceptable salt of the “compounds represented by theabove-mentioned formula [I], the formula [I-1] and the formula [I-2]”(hereinafter to be also referred to as the compound of the presentinvention) may be any salt as long as it forms an atoxic salt with thecompound of the present invention. Examples thereof include a salt withan inorganic acid, a salt with an organic acid, a salt with an inorganicbase, a salt with an organic base, a salt with an amino acid and thelike.

Examples of the salt with an inorganic acid include salts withhydrochloric acid, nitric acid, sulfuric acid, phosphoric acid,hydrobromic acid and the like.

Examples of the salt with an organic acid include salts with oxalicacid, malonic acid, maleic acid, citric acid, fumaric acid, lactic acid,malic acid, succinic acid, tartaric acid, acetic acid, trifluoroaceticacid, gluconic acid, ascorbic acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid and the like.

Examples of the salt with an inorganic base include sodium salt,potassium salt, calcium salt, magnesium salt, ammonium salt and thelike.

Examples of the salt with an organic base include salts withmethylamine, diethylamine, trimethylamine, triethylamine, ethanolamine,diethanolamine, triethanolamine, ethylenediamine,tris(hydroxymethyl)methylamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, guanidine, pyridine, picoline, choline,cinchonine, meglumine and the like.

Examples of the salt with an amino acid include salts with lysine,arginine, aspartic acid, glutamic acid and the like.

Each salt can be obtained by reacting a compound represented by theformula [I], the formula [I-1] and the formula [I-2] with an inorganicbase, an organic base, an inorganic acid, an organic acid or an aminoacid according to a method known per se.

In the present invention, as the pharmaceutically acceptable salt of thecompounds represented by the formula [I], the formula [I-1] and theformula [I-2], preferred are salts with hydrochloric acid (e.g., 1hydrochloride, 2 hydrochloride), salts with hydrobromic acid (e.g., 1hydrobromide, 2 hydrobromide), and sodium salt.

The “solvate” is a compound represented by the formula [I], the formula[I-1] and the formula [I-2] or a pharmaceutically acceptable saltthereof, with which a molecule of a solvent is coordinated, and alsoencompasses hydrates (also referred to as water-containing compound).The solvate is preferably a pharmaceutically acceptable solvate, such asa 1 hydrate, a ½ hydrate, a 2 hydrate, a 1 hydrate of sodium salt, a 1methanolate, a 1 ethanolate, a 1 acetonitrilate, a ⅔ ethanolate of 2hydrochloride of the compound represented by the formula [I], theformula [I-1] and the formula [I-2] and the like.

A solvate of a compound represented by the formula [I], the formula[I-1] and the formula [I-2] or a pharmaceutically acceptable saltthereof can be obtained according to a method known per se.

In addition, there can be various isomers of compounds represented bythe above-mentioned formulas [I], [I-1] and [I-2]. For example, when Eform and Z form are present as geometric isomers, and when an asymmetriccarbon atom is present, enantiomers and diastereomers are present asstereo isomers based on them. In addition, when axial chirality ispresent, stereo isomers based thereon are present. Where necessary,tautomers can be present. Accordingly, all of such isomers and mixturesthereof are encompassed in the scope of the present invention. As thecompound of the present invention, one isolated and purified fromvarious isomers, by-products, metabolites or prodrugs is preferable, andone having a purity of not less than 90% is preferable and one having apurity of not less than 95% is more preferable.

In addition, the compounds represented by the formula [I], the formula[I-1] and the formula [I-2] may be crystal or amorphous.

In addition, a compound represented by the formula [I], the formula[I-1] and the formula [I-2] may be labeled with an isotope (e.g., ³H,¹⁴C, ³⁵S etc.).

As the compounds represented by the formula [I], the formula [I-1] andthe formula [I-2] or a pharmaceutically acceptable salt thereof, or asolvate thereof, compounds represented by the formula [I], the formula[I-1] and the formula [I-2] or a pharmaceutically acceptable saltthereof, or a solvate thereof, which is substantially purified, ispreferable. More preferred is compounds represented by the formula [I],the formula [I-1] and the formula [I-2] or a pharmaceutically acceptablesalt thereof, or a solvate thereof, which has been purified to a purityof not less than 80%.

In the present invention, a prodrug of a compound represented by theformula [I], the formula [I-1] and the formula [I-2] can also be auseful medicament.

A “prodrug” is a derivative of the compound of the present invention,which has a chemically or metabolically decomposable group and whichrestores to the original compound to show its inherent efficacy afteradministration to the body by, for example, hydrolysis, solvolysis ordecomposition under physiological conditions. It includes a complex anda salt, not involving a covalent bond.

The prodrug is utilized, for example, for improving absorption by oraladministration or targeting of a target site.

Examples of the site to be modified include highly reactive functionalgroups in the compound of the present invention, such as hydroxyl group,carboxyl group, amino group and the like.

Examples of the hydroxyl-modifying group include acetyl group, propionylgroup, isobutyryl group, pivaloyl group, palmitoyl group, benzoyl group,4-methylbenzoyl group, dimethylcarbamoyl group,dimethylaminomethylcarbonyl group, sulfo group, alanyl group, fumarylgroup and the like. In addition, a sodium salt of 3-carboxybenzoylgroup, 2-carboxyethylcarbonyl group and the like can also be used.

Examples of the carboxyl-modifying group include methyl group, ethylgroup, propyl group, isopropyl group, butyl group, isobutyl group,tert-butyl group, pivaloyloxymethyl group, carboxymethyl group,dimethylaminomethyl group, 1-(acetyloxy) ethyl group,1-(ethoxycarbonyloxy)ethyl group, 1-(isopropyloxycarbonyloxy)ethylgroup, 1-(cyclohexyloxycarbonyloxy) ethyl group,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, benzyl group, phenylgroup, o-tolyl group, morpholinoethyl group, N,N-diethylcarbamoylmethylgroup, phthalidyl group and the like.

Examples of the amino-modifying group include hexylcarbamoyl group,3-methylthio-1-(acetylamino)propylcarbonyl group,1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group and the like.

Examples of the “pharmaceutical composition” include oral preparationssuch as tablet, capsule, granule, powder, troche, syrup, emulsion,suspension and the like, and parenteral agents such as externalpreparation, suppository, injection, eye drop, transnasal agent,pulmonary preparation and the like.

The pharmaceutical composition of the present invention (e.g., ananti-HIV composition, a pharmaceutical composition for HIV integraseinhibitory etc.) is produced by appropriately admixing a suitable amountof a compound represented by the formula [I], the formula [I-1] or theformula [I-2] of the present invention or a salt thereof, or a solvatethereof with at least one kind of a pharmaceutically acceptable carrieraccording to a method known per se in the technical field ofpharmaceutical preparations. The content of the compound represented bythe formula [I], the formula [I-1] or the formula [I-2] of the presentinvention or a salt thereof, or a solvate thereof in the pharmaceuticalcomposition varies depending on the dosage form, the dose and the like,and the like. It is, for example, 0.1 to 100 wt % of the wholecomposition.

Examples of the “pharmaceutically acceptable carrier” include variousorganic or inorganic carrier substances conventionally used aspreparation materials such as excipient, disintegrant, binder,fluidizer, lubricant and the like for solid dosage forms, and solvent,solubilizing agent, suspending agent, isotonicity agent, bufferingagent, soothing agent and the like for liquid preparations. Wherenecessary, additives such as preservative, antioxidant, colorant,sweetening agent and the like are used.

Examples of the “excipient” include lactose, sucrose, D-mannitol,D-solbitol, cornstarch, dextrin, microcrystalline cellulose, crystallinecellulose, carmellose, carmellose calcium, sodium carboxymethyl starch,low-substituted hydroxypropylcellulose, gum arabic and the like.

Examples of the “disintegrant” include carmellose, carmellose calcium,carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium,crospovidone, low-substituted hydroxypropylcellulose,hydroxypropylmethylcellulose, crystalline cellulose and the like.

Examples of the “binder” include hydroxypropylcellulose,hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose,dextrin, starch, gelatin, carmellose sodium, gum arabic and the like.

Examples of the “fluidizer” include light anhydrous silicic acid,magnesium stearate and the like.

Examples of the “lubricant” include magnesium stearate, calciumstearate, talc and the like.

Examples of the “solvent” include purified water, ethanol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the “solubilizing agent” include propylene glycol,D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate,sodium citrate and the like.

Examples of the “suspending agent” include benzalkonium chloride,carmellose, hydroxypropylcellulose, propylene glycol, povidone,methylcellulose, glycerol monostearate and the like.

Examples of the “isotonicity agent” include glucose, D-sorbitol, sodiumchloride, D-mannitol and the like.

Examples of the “buffering agent” include sodium hydrogen phosphate,sodium acetate, sodium carbonate, sodium citrate and the like.

Examples of the “soothing agent” include benzyl alcohol and the like.

Examples of the “preservative” include ethyl parahydroxybenzoate,chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid andthe like.

Examples of the “antioxidant” include sodium sulfite, ascorbic acid andthe like.

Examples of the “colorant” include food colors (e.g., Food Color Red No.2 or 3, Food Color yellow 4 or 5 etc.), β-carotene and the like.

Examples of the “sweetening agent” include saccharin sodium, dipotassiumglycyrrhizinate, aspartame and the like.

The pharmaceutical composition of the present invention can beadministered not only to human but also to mammals other than human(e.g., mouse, rat, hamster, guinea pig, rabbit, cat, dog, swine, bovine,horse, sheep, monkey etc.) orally or parenterally (e.g., topical,rectal, intravenous administration etc.). While the dose variesdepending on the subject of administration, disease, symptom, dosageform, administration route and the like, for example, the dose for oraladministration to an adult patient (body weight: about 60 kg) isgenerally within the scope of about 1 mg to 1 g per day, based on thecompound of the present invention as an active ingredient. The amountcan be administered in one to several portions.

The compounds represented by the above-mentioned formula [I], theformula [I-1] and the formula [I-2] or a pharmaceutically acceptablesalt thereof, or a solvate thereof inhibits HIV integrase, and can beused as an active ingredient of a therapeutic agent or prophylacticagent for HIV infection.

To “inhibit HIV integrase” means to specifically inhibit the function asHIV integrase to eliminate or attenuate the activity thereof. Forexample, it means to specifically inhibit the function of HIV integraseunder the conditions of the below-mentioned Experimental Example 1. Asthe “inhibition of HIV integrase”, preferred is “inhibition of human HIVintegrase”. As the “HIV integrase inhibitor”, preferred is a “human HIVintegrase inhibitor”.

The compounds represented by the above-mentioned formula [I], theformula [I-1] and the formula [I-2] or a pharmaceutically acceptablesalt thereof, or a solvate thereof can be used in combination(hereinafter to be referred to as combination use) with other single orplural medicaments (hereinafter to be also referred to as a concomitantdrug) by a conventional method generally employed in the medicamentfield.

The administration frequency of the compounds represented by theabove-mentioned formula [I], the formula [I-1] and the formula [I-2], ora pharmaceutically acceptable salt thereof, or a solvate thereof, and aconcomitant drug is not limited, and they may be administered as acombined agent to the subject of administration, or the two may beadministered simultaneously or at certain time intervals. In addition,they may be used as a medicament in the form of a kit containing thepharmaceutical composition of the present invention and a concomitantdrug. The dose of the concomitant drug may be determined according tothe dosage used clinically, and can be appropriately determineddepending on the subject of administration, disease, symptom, dosageform, administration route, administration time, combination and thelike. The administration form of the concomitant drug is notparticularly limited, and the compound of the present invention or asalt thereof, or a solvate thereof and the concomitant drug need only becombined.

An anti-HIV agent is generally required to sustain its effect for a longtime, so that can be effective not only for temporal suppression ofviral growth but also prohibition of viral re-growth. This means that aprolonged administration is necessary and that a high single dose may befrequently inevitable to sustain effect for a longer period through thenight. Such prolonged and high dose administration increases the risk ofcausing side effects.

In view of this, one of the preferable embodiments of the compound ofthe present invention is such compound permitting high absorption byoral administration, and such compound capable of maintaining bloodconcentration of the administered compound for an extended period oftime.

In addition to the above-mentioned, preferable embodiments of thecompound of the present invention are a compound having finepharmacological activity (e.g., a compound having strong HIV integraseinhibitory activity, a compound having high anti-HIV activity), acompound having fine bioavailability (e.g., a compound having highcellular membrane permeability, a compound stable to metabolic enzyme, acompound with low binding ability to protein and the like), a compoundhaving an anti-HIV activity against HIV having G140S/Q148H mutation, andthe like.

Of the compounds of the present invention, a compound having highpharmacological activity (concretely, IC₅₀ of HIV integrase inhibitoryactivity is less than 0.1 μM, preferably less than 0.01 μM) and highoral absorption, whose blood concentration is maintained for a long timeafter administration, is more preferable.

Using the above-mentioned compound, dose and/or frequency ofadministration of the compound of the present invention to human are/isexpected to be decreased. Preferable administration frequency is notmore than twice a day, more preferably, not more than once a day (e.g.,once a day, once in two days, etc.).

The compound of the present invention can be used for the improvement ofviremia due to HIV and/or maintenance of improved condition thereof,prophylaxis and treatment of virus infections, particularly, an HIVinfection and/or maintenance of improved condition thereof.

As an index of the “treatment”, “improvement” or “effect”, a decrease inthe virus level or HIV RNA level in the body, particularly in blood, canbe used.

The “prophylaxis of HIV infection” includes administration of amedicament to a person with suspected or possible HIV infection(infection due to transfusion, infection from mother to child), and thelike.

By the “prophylaxis of AIDS” is meant, for example, administration of amedicament to an individual who tested HIV positive but has not yetdeveloped the disease state of AIDS; administration of a medicament toan individual who shows an improved disease state of AIDS aftertreatment but who carries HIV still to be eradicated and whose relapseof AIDS is worried; administration of a medicament before infection withHIV out of a fear of possible infection; and the like.

Examples of the “other anti-HIV agents” and “other anti-HIV activesubstances” to be used for a multiple drug combination therapy includean anti-HIV antibody or other antibody, an HIV vaccine or other vaccine,immunostimulants such as interferon, interferon agonist and the like, aribozyme against HIV, an HIV antisense drug, an HIV reversetranscriptase inhibitor, an HIV protease inhibitor, an HIV integraseinhibitor, an inhibitor of attachment between a receptor (CD4, CXCR4,CCR5 and the like) of a host cell recognized by virus and the virus(CCR5 antagonist and the like), a DNA polymerase inhibitor or DNAsynthesis inhibitor, a medicament acting on HIVp24, an HIV fusioninhibitor, an IL-2 agonist or antagonist, a TNF-α antagonist, anα-glucosidase inhibitor, a purine nucleoside phosphorylase inhibitor, anapoptosis agonist or inhibitor, a cholinesterase inhibitor, animmunomodulator and the like.

Specific examples of the HIV reverse transcriptase inhibitor includeRetrovir® (zidovudine), Epivir® (lamivudine), Zerit® (sanilvudine),Videx® (didanosine), Hivid® (zalcitabine), Ziagen® (abacavir sulfate),Viramune® (nevirapine), Stocrin® (efavirenz), Rescriptor® (delavirdinemesylate), Combivir® (zidovudine+lamivudine), Trizivir® (abacavirsulfate+lamivudine+zidovudine), Coactinon® (emivirine), Phosphonovir®,Coviracil®, alovudine (3′-fluoro-3′-deoxythymidine), Thiovir(thiophosphonoformic acid), Capravirin(5-[(3,5-dichlorophenyl)thio]-4-isopropyl-1-(4-pyridylmethyl)imidazole-2-methanol carbamic acid), Tenofovir disoproxil fumarate((R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acidbis(isopropoxycarbonyloxymethyl)ester fumarate), DPC-083((4S)-6-chloro-4-[(1E)-cyclopropylethenyl]-3,4-dihydro-4-trifluoromethyl-2(1H)-quinazolinone),DPC-961((4S)-6-chloro-4-(cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone),DAPD ((−)-β-D-2,6-diaminopurine dioxolane), Immunocal, MSK-055, MSA-254,MSH-143, NV-01, TMC-120, DPC-817, GS-7340, TMC-125, SPD-754, D-A4FC,capravirine, UC-781, emtricitabine, alovudine, Phosphazid, BCH-10618,DPC-083, Etravirine, BCH-13520, MIV-210, Abacavir sulfate/lamivudine,GS-7340, GW-5634, GW-695634, TMC-278 and the like, wherein ® means aregistered trademark (hereinafter the same) and the names of othermedicaments are general names.

Specific examples of the HIV protease inhibitor include Crixivan®(indinavir sulfate ethanolate), saquinavir, Invirase® (saquinavirmesylate), Norvir® (ritonavir), Viracept® (nelfinavir mesylate),lopinavir, Prozei® (amprenavir), Kaletra® (ritonavir+lopinavir),mozenavir dimesylate([4R-(4α,5α,6β)]-1,3-bis[(3-aminophenyl)methyl]-hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-onedimethanesulfonate), tipranavir(3′-[(1R)-1-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-phenylethyl-6-propyl-2H-pyran-3-yl]propyl]-5-(trifluoromethyl)-2-pyridinesulfonamide),lasinavir(N-[5(S)-(tert-butoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxybenzyl)hexanoyl]-L-valine2-methoxyethylenamide), KNI-272((R)—N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N-1(R)-2-N-(isoquinolin-5-yloxyacetyl)amino-3-methylthiopropanoyl]amino-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide),GW-433908, TMC-126, DPC-681, buckminsterfullerene, MK-944A (MK944(N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-[4-(2-benzo[b]furanylmethyl)-2(S)-(tert-butylcarbamoyl)piperazin-1-yl]pentanamide)+indinavirsulfate), JE-2147([2(S)-oxo-4-phenylmethyl-3(S)-[(2-methyl-3-oxy)phenylcarbonylamino]-1-oxabutyl]-4-[(2-methylphenyl)methylamino]carbonyl-4(R)-5,5-dimethyl-1,3-thiazole),BMS-232632 (dimethyl(3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedicarboxylate),DMP-850((4R,5S,6S,7R)-1-(3-amino-1H-indazol-5-ylmethyl)-4,7-dibenzyl-3-butyl-5,6-dihydroxyperhydro-1,3-diazepin-2-one),DMP-851, RO-0334649, Nar-DG-35, R-944, VX-385, TMC-114, Tipranavir,Fosamprenavir sodium, Fosamprenavir calcium, Darunavir, GW-0385, R-944,RO-033-4649, AG-1859 and the like.

The HIV integrase inhibitor is exemplified by S-1360, L-870810 and thelike, the DNA polymerase inhibitor or DNA synthesis inhibitor isexemplified by Foscavir®, ACH-126443(L-2′,3′-didehydro-dideoxy-5-fluorocytidine), entecavir((1S,3S,4S)-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]guanine),calanolide A([10R-(10α,11β,12α)]-11,12-dihydro-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-2H,6H,10H-benzo[1,2-b:3,4-b′:5,6-b″]tripyran-2-one),calanolide B, NSC-674447 (1,1′-azobisformamide), Iscador (viscum alubmextract), Rubitecan and the like, the HIV antisense drug is exemplifiedby HGTV-43, GEM-92 and the like, the anti-HIV antibody or other antibodyis exemplified by NM-01, PRO-367, KD-247, Cytolin®, TNX-355 (CD4antibody), AGT-1, PRO-140 (CCR5 antibody), Anti-CTLA-4MAb and the like,the HIV vaccine or other vaccine is exemplified by ALVAC®, AIDSVAX®,Remune®, HIV gp41 vaccine, HIV gp120 vaccine, HIV gp140 vaccine, HIVgp160 vaccine, HIV p17 vaccine, HIV p24 vaccine, HIV p55 vaccine,AlphaVax Vector System, canarypox gp160 vaccine, AntiTat, MVA-F6 Nefvaccine, HIV rev vaccine, C4-V3 peptide, p2249f, VIR-201, HGP-30W,TBC-3B, PARTICLE-3B, Antiferon (interferon-α vaccine) and the like, theinterferon or interferon agonist is exemplified by Sumiferon®,MultiFeron®, interferon-τ, Reticulose, human leukocyte interferon α andthe like, the CCR5 antagonist is exemplified by SCH-351125 and the like,the medicament acting on HIV p24 is exemplified by GPG-NH2(glycyl-prolyl-glycinamide) and the like, the HIV fusion inhibitor isexemplified by FP-21399(1,4-bis[3-[(2,4-dichlorophenyl)carbonylamino]-2-oxo-5,8-disodiumsulfonyl]naphthyl-2,5-dimethoxyphenyl-1,4-dihydrazone), T-1249,Synthetic Polymeric Construction No3, pentafuside, FP-21399, PRO-542,Enfuvirtide and the like, the IL-2 agonist or antagonist is exemplifiedby interleukin-2, Imunace®, Proleukin®, Multikine®, Ontak® and the like,the TNF-α antagonist is exemplified by Thalomid® (thalidomide),Remicade® (infliximab), curdlan sulfate and the like, the α-glucosidaseinhibitor is exemplified by Bucast® and the like, the purine nucleosidephosphorylase inhibitor is exemplified by peldesine(2-amino-4-oxo-3H,5H-7-[(3-pyridyl)methyl]pyrrolo[3,2-d]pyrimidine) andthe like, the apoptosis agonist or inhibitor is exemplified by Arkin Z®,Panavir®, Coenzyme Q10(2-deca(3-methyl-2-butenylene)-5,6-dimethoxy-3-methyl-p-benzoquinone)and the like, the cholinesterase inhibitor is exemplified by Cognex® andthe like, and the immunomodulator is exemplified by Imunox®, Prokine®,Met-enkephalin(6-de-L-arginine-7-de-L-arginine-8-de-L-valinamide-adrenorphin), WF-10(10-fold dilute tetrachlorodecaoxide solution), Perthon, PRO-542, SCH-D,UK-427857, AMD-070, AK-602, TK-303 (Elvitegravir) and the like.

In addition, Neurotropin®, Lidakol®, Ancer 20®, Ampligen®, Anticort®,Inactivin®, PRO-2000, Rev M10 gene, HIV specific cytotoxic T cell (CTLimmunotherapy, ACTG protocol 080 therapy, CD4-ζ gene therapy), SCAbinding protein, RBC-CD4 complex, Motexafin gadolinium, GEM-92,CNI-1493, (±)-FTC, Ushercell, D2S, BufferGel®, VivaGel®, Glyminoxvaginal gel, sodium lauryl sulfate, 2F5, 2F5/2G12, VRX-496, Ad5gag2,BG-777, IGIV-C, BILR-255 and the like are exemplified.

The compound of the present invention can be combined with one or more(e.g., 1 or 2) kinds of other anti-HIV active substances (to be alsoreferred to as other anti-HIV agents), and used as an anti-HIV agent andthe like for the prophylaxis or treatment of HIV infection. As the“other anti-HIV agents” and “other anti-HIV active substances” to beused for a multiple drug combination therapy with the compound of thepresent invention, preferred are an HIV reverse transcriptase inhibitorand an HIV protease inhibitor. Two or three, or even a greater number ofmedicaments can be used in combination, wherein a combination ofmedicaments having different action mechanisms is one of the preferableembodiments. In addition, selection of medicaments free of side effectduplication is preferable.

Specific examples of the combination of medicaments include acombination of a group consisting of efavirenz, tenofovir,emtricitabine, indinavir, nelfinavir, atazanavir, ritonavir+indinavir,ritonavir+lopinavir, ritonavir+saquinavir, didanosine+lamivudine,zidovudine+didanosine, stavudine+didanosine, zidovudine+lamivudine,stavudine+lamivudine and tenofovir+emtricitabine, and the compound ofthe present invention (Guidelines for the Use of Antiretroviral Agentsin HIV-Infected Adults and Adolescents. Aug. 13, 2001). Particularlypreferred is a combined use of two agents with efavirenz, indinavir,nelfinavir, tenofovir, emtricitabine, zidovudine or lamivudine, and acombined use of three agents with zidovudine+lamivudine,tenofovir+lamivudine, tenofovir+zidovudine, tenofovir+efavirenz,tenofovir+nelfinavir, tenofovir+indinavir, tenofovir+emtricitabine,emtricitabine+lamivudine, emtricitabine+zidovudine,emtricitabine+efavirenz, emtricitabine+nelfinavir,emtricitabine+indinavir, nelfinavir+lamivudine, nelfinavir+zidovudine,nelfinavir+efavirenz, nelfinavir+indinavir, efavirenz+lamivudine,efavirenz+zidovudine or efavirenz+indinavir.

In the case of combined administration, the compound of the presentinvention can be administered simultaneously with a medicament to beused in combination (hereinafter concomitant drug) or administered atcertain time intervals. In the case of combined administration, apharmaceutical composition comprising the compound of the presentinvention and a concomitant drug can be administered. Alternatively, apharmaceutical composition comprising the compound of the presentinvention and a pharmaceutical composition comprising a concomitant drugmay be administered separately. The administration route of the compoundof the present invention and that of the concomitant drug may be thesame or different.

In the case of a combined administration, the compound of the presentinvention can be administered once a day or several times a day in asingle dose of 0.01 mg to 1 g, or may be administered at a smaller dose.The concomitant drug can be administered at a dose generally used forthe prevention or treatment of an HIV infection, for example, at asingle dose of 0.01 mg to 0.3 g. Alternatively, it may be administeredin a smaller dose.

Now, production methods of the compound of the present invention arespecifically explained. However, the present invention is not limited tothese production methods. For production of the compound of the presentinvention, the order of reactions can be appropriately changed. Thereactions may be performed from a reasonable step or a reasonablesubstitution moiety. In addition, an appropriate substituent conversion(conversion or further modification of substituent) step may be insertedbetween respective steps. When a reactive functional group is present,protection and deprotection may be appropriately performed. Furthermore,to promote the progress of reactions, reagents other than thoseexemplified below may be used as appropriate. The starting compoundswhose production methods are not described are commercially available orcan be easily prepared by a combination of known synthesis reactions.The compound obtained in each step can be purified by conventionalmethods such as distillation, recrystallization, column chromatographyand the like. In some cases, the next step may be performed withoutisolation and purification.

In the following production methods, the “room temperature” means 1 to40° C.

Production Method I Production Method I-1

Of compounds [I-3-1] in the below-mentioned production method I-3,compound [I-1-6] which is compound [I-3-1] wherein Y is CH can besynthesized by the following method.

wherein R^(11a) and R^(11c) are the same or different and each is ahydroxyl-protecting group such as an acetyl group, a benzyl group, amethyl group, an ethyl group, an isopropyl group, a trimethylsilylgroup, a triethylsilyl group, a tert-butyldimethylsilyl group, atriisopropylsilyl group, a tert-butyldiphenylsilyl group and the like,R^(11b) is a carboxyl-protecting group such as a methyl group, an ethylgroup, a benzyl group, a tert-butyl group and the like, X^(11a) is ahalogen atom such as a chlorine atom, a bromine atom and the like, andother symbols are each as described above.

Step 1

Compound [I-1-2] can be obtained by introducing a protecting group intothe carboxyl group of compound [I-1-1] according to a known method.

For example, when R^(11b) is a methyl group, compound [I-1-2] can beobtained by reacting compound [I-1-1] with trimethylsilyldiazomethane ata low temperature to room temperature in a single or mixed solvent suchas tetrahydrofuran (THF), toluene, methanol, ethanol and the like.

Step 2

Compound [I-1-3] can be obtained by introducing a halogen atom X^(11a)into compound [I-1-2] according to a known method.

For example, when X^(11a) is a bromine atom, compound [I-1-3] can beobtained by reacting compound [I-1-2] with a bromination reagent (e.g.,bromine, trimethylphenylammonium tribromide etc.) at room temperature tounder heating in a solvent such as chloroform, methylene chloride,acetic acid and the like.

Step 3

Compound [I-1-4] can be obtained by introducing a protecting group intoa hydroxyl group of compound [I-1-3] according to a known method.

For example, when R^(11c) is a benzyl group, compound [I-1-4] can beobtained by reacting compound [I-1-3] with benzyl halide (e.g., benzylchloride, benzyl bromide etc.) at room temperature to under heating inthe presence of a base such as potassium acetate, potassium carbonate,potassium hydrogen carbonate, sodium hydrogen carbonate, potassiumphosphate, triethylamine, sodium hydrogen phosphate, cesium carbonate,sodium hydride, potassium t-butoxide, lithiumdiisopropylamide (LDA) andthe like in a solvent such as N,N-dimethylformamide (DMF),dimethylacetamide (DMA), acetonitrile, 1,2-dimethoxyethane, THF, tolueneand the like.

Step 4

Compound [I-1-6] can be obtained by subjecting compound [I-1-4] to acoupling reaction with compound [I-1-5] in the presence of a palladiumcatalyst (e.g., tris(dibenzylideneacetone)dipalladium(0),tetrakis(triphenylphosphine)palladium(0) andbis(triphenylphosphine)palladium(II) dichloride etc.) at roomtemperature to under heating in a solvent such as DMF, DMA,acetonitrile, toluene, 1,4-dioxane and the like. For preferable progressof the reaction, a ligand (e.g., tri(2-furyl)phosphine,tributylphosphine etc.) may be further added.

For example, compound [I-1-5] wherein n is 1 can be obtained in the samemanner as in step 1R-2 and step 1R-3 of the below-mentioned ReferenceExample 1.

Production Method I-2

Of compounds [I-3-1] in the below-mentioned production method I-3,compound [I-2-9] which is compound [I-3-1] wherein Y is a nitrogen atomand R^(13b) is an ethyl group can be synthesized by the followingmethod.

wherein R^(12a) is a hydroxyl-protecting group such as acetyl group,benzyl group, methyl group, ethyl group, isopropyl group, trimethylsilylgroup, triethylsilyl group, tert-butyldimethylsilyl group,triisopropylsilyl group, tert-butyldiphenylsilyl group and the like,R^(12b) is a carboxyl-protecting group such as methyl group, ethylgroup, benzyl group, tert-butyl group and the like, and other symbolsare each as described above.

Step 1

Compound [I-2-3] can be obtained by reacting compound [I-2-1] withcompound [I-2-2] at −78° C. to room temperature conditions in a solventsuch as DMF, DMA, dimethyl sulfoxide (DMSO), THF, toluene and the like,in the presence of a base such as sodium hydride,lithiumdiisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS) andthe like.

Step 2

Compound [I-2-4] can be obtained by reacting Compound [I-2-3] withN,N-dimethylformamidedimethylacetal at room temperature to under heatingin a solvent such as DMF, acetonitrile, THF, chloroform, ethyl acetate,methylene chloride, toluene and the like.

Step 3

Compound [I-2-6] can be obtained by adding a base such as sodiumhydride, LDA, LHMDS and the like to a solution of Compound [I-2-4]dissolved in a solvent such as DMF, DMA, DMSO, THF, toluene and the likeat -78° C. to room temperature, reacting the compound with compound[I-2-5] and treating same with triethylamine, diisopropylethylamine orthe like.

Step 4

Compound [I-2-7] can be obtained by removing the carboxyl-protectinggroup R^(12b) of compound [I-2-6] by a known method. For example, whenthe protecting group is a tert-butyl group, compound [I-2-7] can beobtained by stirring compound [I-2-6] at a low temperature to underheating in a single or mixed solvent of hexane, chloroform, methylenechloride, ethyl acetate, toluene, 1,2-dimethoxyethane, 1,4-dioxane, THF,methanol, ethanol, 2-propanol, DMSO, DMF, DMA, acetonitrile, water andthe like in the presence of acid such as p-toluenesulfonic acid,methanesulfonic acid, boron trifluoride, boron trichloride, borontribromide, aluminum trichloride, hydrochloric acid, hydrogen bromide,phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid andthe like.

Step 5

Compound [I-2-9] can be obtained by converting compound [I-2-7] to acidchloride by a known method, and further reacting the compound withcompound [I-2-8]. Specifically, compound [I-2-9] can be obtained byconverting compound [I-2-7] to acid chloride with a chlorinating agentsuch as oxalyl chloride, thionyl chloride, phosphorus trichloride andthe like at a low temperature to room temperature in a single or mixedsolvent of hexane, chloroform, methylene chloride, ethyl acetate,toluene, 1,2-dimethoxyethane, 1,4-dioxane, THF and the like in thepresence of a catalytic amount of DMF where necessary, and reacting thecompound with compound [I-2-8].

Production Method I-3

A compound represented by the above-mentioned formula [I] can besynthesized by the following method.

wherein R^(13a) is a hydroxyl-protecting group such as acetyl group,benzyl group, methyl group, ethyl group, isopropyl group, trimethylsilylgroup, triethylsilyl group, tert-butyldimethylsilyl group,triisopropylsilyl group, tert-butyldiphenylsilyl group and the like,R^(13b) is a carboxyl-protecting group such as methyl group, ethylgroup, benzyl group, tert-butyl group and the like, R^(13c) is anamino-protecting group such as benzyloxycarbonyl group,tert-butoxycarbonyl group, benzyl group and the like, and other symbolsare each as described above.

Step 1

Compound [I-3-3] can be obtained by reacting compound [I-3-1] withcompound [I-3-2], wherein amino-protecting group R^(13c) is removed inadvance according to a known method at room temperature to under heatingin a single or mixed solvent of chloroform, dichloromethane, DMF, DMA,DMSO, acetonitrile, 1,2-dimethoxyethane, THF, toluene, water and thelike, and cyclizing the compound in the presence of a base such astriethylamine, diisopropylamine, diisopropylethylamine,diazabicycloundecene, sodium carbonate, potassium carbonate, sodiumhydrogen carbonate and the like. The cyclization reaction can also beperformed in the presence of acid such as acetic acid, p-toluenesulfonicacid, methanesulfonic acid, boron trifluoride, boron trichloride, borontribromide, hydrochloric acid, hydrogen bromide, phosphoric acid,sulfuric acid and the like.

Step 2

Compound [I] can be obtained by removing the hydroxyl-protecting groupR^(13a) of compound [I-3-3] by a known method. For example, when theprotecting group is a benzyl group, compound [I] can be obtained bystirring compound [I-3-3] at a low temperature to room temperature in asingle or mixed solvent of hexane, chloroform, methylene chloride, ethylacetate, toluene, methanol, ethanol, 2-propanol, THF, 1,4-dioxane,acetonitrile, water and the like, in the presence of acid such ashydrochloric acid, sulfuric acid, hydrogen bromide, phosphoric acid,acetic acid, trifluoroacetic acid and the like. The acid may be used asa solvent.

Production Method I-4

Compound [I-3-2] in the above-mentioned production method I-3(corresponding to the following compound [I-4-3]) can be synthesized bythe following method.

wherein R^(14a) is an amino-protecting group such as benzyloxycarbonylgroup, tert-butoxycarbonyl group, benzyl group and the like, and othersymbols are each as described above.

Step 1

Compound [I-4-1] obtainable from a commercially available compound by aknown method is reacted with phthalimide at a low temperature to underheating in a single or mixed solvent of THF, methylene chloride,chloroform, DMF, ethyl acetate, toluene and the like in the presence ofa phosphorus reagent such as triphenylphosphine,diphenyl(2-pyridyl)phosphine, tributylphosphine, tri-tert-butylphosphineand the like and an azo compound such as diisopropylazodicarboxylate,diethylazodicarboxylate, N,N,N′,N′-tetramethylazodicarboxamide,1,1′-(azodicarbonyl)dipiperidine and the like, and the obtained compoundis further treated with hydrazine to remove a phthaloyl group to giveamine compound [I-4-2].

Step 2

Compound [I-4-2] is reacted with a ketone compound or aldehyde compoundat a low temperature to room temperature in a solvent such as DMF,acetonitrile, THF, chloroform, ethyl acetate, methylene chloride,toluene and the like, and the mixture is stirred in the presence of areducing agent such as sodium borohydride, sodium triacetoxyborohydrideand the like to introduce substituent R¹ into the amino group ofcompound [I-4-2], whereby compound [I-4-3] can be obtained.

Production Method I-5

Of compounds [I-3-2] in the above production method I-3, a compound,which is compound [I-3-2] wherein particularly R² and R³ are each ahydrogen atom, one of R⁴ and R⁵ is a carboxyl group or —CO—NR^(a)R^(b)wherein R^(a) and R^(b) are as described above, and the other is a C₁₋₆alkyl group optionally substituted by the same or different 1 to 5substituents selected from the aforementioned group A, can besynthesized by the following method.

wherein R^(15a) is an amino-protecting group such as benzyloxycarbonylgroup, tert-butoxycarbonyl group, benzyl group and the like, R^(15b) isa carboxyl-protecting group such as methyl group, ethyl group, benzylgroup, tert-butyl group and the like, R^(15c) is a C₁₋₆ alkyl groupoptionally substituted by the same or different 1 to 5 substituentsselected from the aforementioned group A, and other symbols are each asdescribed above.

Step 1

Compound [I-5-2] can be obtained by oxidizing the hydroxyl group ofcompound [I-5-1] obtainable from a commercially available compound by aknown method, to a aldehyde group by a chromium oxide-pyridine complex(e.g., pyridinium chlorochromate, pyridinium dichromate and the like), ametal oxidant (e.g., chromium oxide, silver carbonate, manganese dioxideand the like), by DMSO oxidization using various DMSO activators such asoxalyl chloride, trifluoroacetic anhydride, acetic anhydride,dicyclohexylcarbodiimide (DCC), sulfur trioxide-pyridine complex and thelike, Dess-Martin oxidization and the like according to a known method.

Step 2

Compound [I-5-3] can be obtained by subjecting the aldehyde group ofcompound [I-5-2] to a reductive amination under similar conditions as inproduction method I-4, step 2. The obtained compound [I-5-3] is cyclizedby the above-mentioned method, and the carboxyl-protecting group R^(15b)is removed by a known method and, where necessary, the resultingcompound is reacted with an amine compound by a known method to give theobject compound.

Production method II

Production Method II-1

Of the compounds represented by the above-mentioned formula [I],compound [II-1-6], which is compound [I] wherein Y is CH can besynthesized by the following method.

wherein R^(21a) is a hydroxyl-protecting group such as acetyl group,benzyl group, methyl group, ethyl group, isopropyl group, trimethylsilylgroup, triethylsilyl group, tert-butyldimethylsilyl group,triisopropylsilyl group, tert-butyldiphenylsilyl group and the like,R^(21b) is an amino-protecting group such as benzyloxycarbonyl group,tert-butoxycarbonyl group, benzyl group and the like, X^(21a) is aleaving group such as a halogen atom (e.g., fluorine atom, chlorineatom, bromine atom, iodine atom and the like), p-toluenesulfonyloxygroup (OTs), methanesulfonyloxy group (OMs), trifluoromethanesulfonyloxygroup (OTf) and the like, and other symbols are each as described above.

Step 1

Compound [II-1-3] can be obtained by converting compound [II-1-1] toacid chloride by a known method at a low temperature to under heating,reacting the acid chloride with compound [II-1-2], removing theamino-protecting group R^(21b), and stirring the mixture in the presenceof a base such as potassium acetate, potassium carbonate, potassiumhydrogen carbonate, sodium hydrogen carbonate, potassium phosphate,triethylamine, diisopropylethylamine, sodium hydrogen phosphate, cesiumcarbonate and the like.

Compound [II-1-2] can be obtained by a method similar to that ofProduction method I-4.

Step 2

Compound [II-1-4] can be obtained by introducing leaving group X^(21a)into compound [II-1-3] by a known method.

For example, when the leaving group X^(21a) is a bromine atom, thebromine atom is introduced into compound [II-1-3] by a method similar tothat in production method I-1, step 2 to give compound [II-1-4].

Step 3

Compound [II-1-4] is reacted with compound [II-1-5] by a method similarto that of production method I-1, step 4, and the hydroxyl-protectinggroup R^(21a) is removed by a method similar to that of productionmethod I-3, step 2, whereby compound [II-1-6] can be obtained.

Production Method I-2

Of the compounds represented by the above-mentioned formula [I], acompound, which is compound [I] wherein particularly R² and R³ are eacha hydrogen atom, and one of R⁴ and R⁵ is a methyl group substituted by—NR^(A3)R^(A4) wherein R^(A3) and ^(A4) are as described above, and theother is a C₁₋₆ alkyl group optionally substituted by the same ordifferent 1 to 5 substituents selected from the aforementioned group A,can be synthesized by the following method.

wherein R^(22a) is an amino-protecting group such as benzyloxycarbonylgroup, tert-butoxycarbonyl group, benzyl group and the like, R^(22b) isa C₁₋₆ alkyl group optionally substituted by the same or different 1 to5 substituents selected from the aforementioned group A, R^(22a) andR^(22d) are the same or different, and each is a hydroxyl-protectinggroup such as acetyl group, benzyl group, methyl group, ethyl group,isopropyl group, trimethylsilyl group, triethylsilyl group,tert-butyldimethylsilyl group, triisopropylsilyl group,tert-butyldiphenylsilyl group and the like, and other symbols are eachas described above.

Step 1

The hydroxyl group of compound [II-2-1] is oxidized, by a known methodto give aldehyde group, whereby compound [II-2-2] can be obtained. Theknown method is the same as the one indicated for, for example, theproduction method I-5, step 1.

Step 2

Compound [II-2-3] can be obtained by subjecting compound [II-2-2] toreductive amination by the same method as in the production method I-5,step 2.

Step 3

Compound [II-2-4] can be obtained from compound [II-2-3] by the samemethod as in production method II-1, step 1 to step 3.

Step 4

The hydroxyl-protecting group R^(22c) of compound [II-2-4] is removed bya known method, and the hydroxyl group is appropriately subjected tosubstituent conversion to a leaving group (OTs, OMs, OTf etc.). Afterreaction with potassium phthalimide, and the phthaloyl group is removedby a method similar to production method I-4, step 1 to give compound[II-2-5]. The obtained compound [II-2-5] is subjected to anappropriately combination of removal of hydroxyl-protecting groupR^(22d) by a method similar to production method I-3, step 2, andmodification of amino group of compound [II-2-5] by a known method togive the object compound.

Production Method III

Of compounds represented by the above-mentioned formula [I], compound[III-1-9], which is compound [I] wherein Y is a nitrogen atom can besynthesized by the following method.

wherein R^(31a) is a hydroxyl-protecting group such as acetyl group,benzyl group, methyl group, ethyl group, isopropyl group, trimethylsilylgroup, triethylsilyl group, tert-butyldimethylsilyl group,triisopropylsilyl group, tert-butyldiphenylsilyl group and the like,R^(31b) and R^(31c) are the same or different and each is acarboxyl-protecting group such as methyl group, ethyl group, benzylgroup, tert-butyl group and the like, and other symbols are each asdescribed above.

Step 1

Compound [III-1-3] can be obtained by reacting compound [III-1-1] withcompound [III-1-2] by a method similar to production method I-2, step 3.

Step 2

Compound [III-1-4] can be obtained by removing the carboxyl-protectinggroup R^(31b) of compound [III-1-3] by a method similar to productionmethod I-2, step 4.

Step 3

Compound [III-1-5] can be obtained by reacting compound [III-1-4] withcompound [I-2-8] by a method similar to production method I-2, step 5.

Step 4

Compound [III-1-6] can be obtained by removing the carboxyl-protectinggroup R^(31c) of compound [III-1-5] by a known method.

Step 5

Compound [III-1-7] can be obtained by converting compound [III-1-6] toacid chloride by a method similar to production method I-2, step 5, andreacting the acid chloride with compound [I-3-2] in a solvent such ashexane, chloroform, methylene chloride, ethyl acetate, toluene,1,2-dimethoxyethane, 1,4-dioxane, THF and the like in the presence of abase such as potassium acetate, potassium carbonate, potassium hydrogencarbonate, sodium hydrogen carbonate, potassium phosphate,triethylamine, diisopropylethylamine, sodium hydrogen phosphate, cesiumcarbonate and the like.

Step 6

Compound [III-1-8] can be obtained by removing the amino-protectinggroup R^(13c) of compound [III-1-7] by a known method, and performingcyclization by a method similar to a cyclization reaction of productionmethod II-1, step 1 in the presence of a base.

Step 7

Compound [III-1-9] can be obtained by removing the hydroxyl-protectinggroup R^(31a) of compound [III-1-8] by a known method. For example, whenthe protecting group is a benzyl group, a method similar to productionmethod I-3, step 2 can be used.

EXAMPLES

Now, the production methods of the compound of the present invention arespecifically explained by referring to Examples, which are not to beconstrued as limitative.

The abbreviations used in the Examples mean the following.

-   Bn: benzyl group-   Boc: tert-butoxycarbonyl group-   Et: ethyl group-   Me: methyl group-   Ms: methanesulfonyl group-   TBS: tert-butyldimethylsilyl group-   TFA: trifluoroacetic acid-   THP: tetrahydropyranyl group-   Z: benzyloxycarbonyl group

In addition, the following ¹H-NMR values were measured by resolution 400MHz.

Reference Example 1 Step 1R-1

3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (11.43 g) was suspended inmethanol (20 mL)-tetrahydrofuran (80 mL), 2M(trimethylsilyl)diazomethane/hexane solution (46.4 mL) was addeddropwise under ice-cooling, and the mixture was stirred at roomtemperature for 1.5 hr. The solvent was evaporated under reducedpressure and the obtained residue was dissolved in chloroform (80 mL).Thereto was added bromine (23 mL) and the mixture was stirred for 2 daysat 75° C. The mixture was allowed to cool to room temperature, hexanewas added and the precipitated solid was collected by filtration. Theobtained solid was dissolved in dimethylformamide (54 mL), potassiumcarbonate (7.1 g) and benzyl bromide (5.6 mL) were added, and themixture was stirred at 80° C. for 40 min. The mixture was allowed tocool to room temperature and filtered. The filtrate was concentrated and1N aqueous hydrochloric acid solution was added to the obtained residue.The mixture was extracted twice with ethyl acetate. The combined ethylacetate layer was washed with saturated brine, dried, and concentrated.The concentrate was purified by silica gel column chromatography (ethylacetate:hexane=1:20-1:4), the eluate was concentrated, and theprecipitated crystals were collected by filtration to give the objectcompound (7.65 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.11 (s, 1H), 7.49-7.44 (m, 2H), 7.40-7.32 (m, 3H),5.32 (s, 2H), 3.89 (s, 3H).

Step 1R-2

To a solution of 2-bromothiazole-5-carbaldehyde (14 g) in THF (300 mL)was added dropwise 1M (4-fluorophenyl)magnesium bromide/THF solution (80mL) at −78° C., and the mixture was stirred for 1 hr. Saturated aqueousammonium chloride solution was added, and the mixture was allowed tocool to room temperature, and extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried, and concentrated.Trifluoroacetic acid (100 mL) and triethylsilane (58 mL) were added tothe obtained residue, and the mixture was stirred for 100 min at 75° C.The mixture was allowed to cool to room temperature and concentrated,and the residue was purified by silica gel column chromatography (ethylacetate:hexane=1:50-1:9) to give the object compound (16.8 g) describedin the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 7.31-7.29 (m, 1H), 7.21-7.14 (m, 2H), 7.05-6.98 (m,2H), 4.07 (s, 2H).

Step 1R-3

To a solution of the compound (3.2 g) obtained in step 1R-2 in THF (50mL) was added dropwise 1.6M n-butyllithium/hexane solution (8.1 mL) at−78° C. and the mixture was stirred for 10 min. Tributyltin chloride(3.5 mL) was added, and the mixture was stirred at −78° C. for 30 minand at room temperature for 30 min. Ice-cold water was added and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried, and concentrated to give the objectcompound (6.2 g) described in the above-mentioned scheme as a crudeproduct.

¹H-NMR (THF) δ: 7.76-7.74 (m, 1H), 7.25-7.21 (m, 2H), 7.03-6.97 (m, 2H),4.19 (s, 2H), 1.65-1.56 (m, 6H), 1.40-1.28 (m, 6H), 1.20-1.13 (m, 6H),0.91-0.85 (m, 9H).

Step 1R-4

Under an argon stream, tris(dibenzylideneacetone)dipalladium(0) (84 mg)and tri(2-furyl)phosphine (85 mg) were suspended in toluene (1.5 mL),and the suspension was stirred at room temperature for 15 min. Thecompound (890 mg) obtained in step 1R-3 and the compound (310 mg)obtained in step 1R-1 were added, and the mixture was stirred at 80° C.for 1 hr. The obtained reaction mixture was filtered through celite, andconcentrated, and the concentrate was purified by silica gel columnchromatography (ethyl acetate:hexane=1:20-1:4) to give the objectcompound (190 mg) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.91 (s, 1H), 7.62-7.61 (m, 1H), 7.51-7.45 (m, 2H),7.40-7.32 (m, 3H), 7.25-7.19 (m, 2H), 7.04-6.97 (m, 2H), 5.37 (s, 2H),4.19 (s, 2H), 3.91 (s, 3H).

Reference Example 2 Step 2R-1

In the same manner as in step 1R-1 except that3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (15.0 g) was ethylated withiodoethane, the object compound (10.97 g) described in theabove-mentioned scheme was obtained.

¹H-NMR (CDCl₃) δ: 8.11 (s, 1H), 7.50-7.46 (m, 2H), 7.40-7.32 (m, 3H),5.31 (s, 2H), 4.36 (q, 2H, J=7.2 Hz), 1.33 (t, 3H, J=7.2 Hz).

Step 2R-2

In the same manner as in step 1R-4, the object compound (1.0 g)described in the above-mentioned scheme was obtained from the compound(1.2 g) obtained in step 2R-1.

¹H-NMR (CDCl₃) δ: 8.91 (s, 1H), 7.62-7.61 (m, 1H), 7.51-7.47 (m, 2H),7.39-7.31 (m, 3H), 7.25-7.20 (m, 2H), 7.04-6.97 (m, 2H), 5.37 (s, 2H),4.38 (q, 2H, J=7.2 Hz), 4.19 (s, 2H), 1.34 (t, 3H, J=7.2 Hz).

Reference Example 3

Step 3R-1

To a solution of 4-fluorophenylacetic acid (25 g) and tert-butylcarbazate (22.5 g) in DMF (200 mL) were added 1-hydroxybenzotriazolehydrate (HOBT.H_(Z)O (27.3 g)) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl(34.1 g)), and the mixture was stirred at room temperature overnight.Saturated aqueous sodium hydrogen carbonate solution was added, and themixture was stirred for a while and extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate,and is concentrated to give the object compound (32.3 g) described inthe above-mentioned scheme as a crude product.

Step 3R-2

To a solution of the compound (32.3 g) obtained in step 3R-1 in THF (300mL) was added a Lawesson reagent (48.7 g), and the mixture was stirredat 50° C. overnight and allowed to cool. The reaction mixture was pouredinto a stirred saturated aqueous sodium hydrogen carbonate solution bysmall portions, and the mixture was stirred at room temperature for 30min. The mixture was extracted twice with ethyl acetate, and the organiclayer was washed with saturated aqueous sodium hydrogen carbonatesolution and saturated brine, dried over magnesium sulfate, andconcentrated. To the residue was added 4N hydrochloric acid/dioxanesolution (300 mL), and the mixture was stirred at room temperature for 1hr. The precipitated salt was collected by filtration, and dissolved inwater (200 mL), and the solution was neutralized with sodium hydrogencarbonate and extracted twice with ethyl acetate. The organic layer waswashed with saturated brine, dried over sodium sulfate, andconcentrated. To the residue was added ethyl acetate/hexane (1:4)solution and the mixture was slurry washed. The residue was collected byfiltration, and dried to give the object compound (15.78 g) described inthe above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.27-8.03 (br m, 1H), 7.26-7.20 (m, 2H), 7.10-7.03 (m,2H), 4.88-4.75 (br m, 2H), 4.08 (s, 2H).

Example 1 Step 1-1

To a solution of (S)-2-ethylamino-3-methoxypropylcarbamic acid benzylester (76 mg) in methanol (10 mL) was added a 7.5% palladium-carboncatalyst (100 mg), and the reaction mixture was stirred under amoderate-pressure (0.4 MPa) in a hydrogen atmosphere at room temperaturefor 3 hr. The reaction mixture was filtered through celite,trifluoroacetic acid (1 mL) was added and the mixture was concentratedto give the object compound (133 mg) described in the above-mentionedscheme as a crude product.

Step 1-2

To a solution of the compound (55 mg) obtained in step 1-1 intetrahydrofuran (1.5 mL) was added diisopropylethylamine (160 μL), andthe mixture was stirred for 10 min. A solution of the compound (46 mg)obtained in Reference Example 2 in tetrahydrofuran (1 mL) was added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was concentrated, toluene (4 mL) and1,8-diazabicyclo[5.4.0]undec-7-ene (200 μL) were added, and the mixturewas stirred at 110° C. for 15 min. Acetic acid (500 μL) was added, andthe mixture was stirred at 110° C. for 1 hr. The reaction mixture wasallowed to cool to room temperature, and diluted with ethyl acetate. Themixture was washed with 5% aqueous potassium hydrogen sulfate solution,dried and concentrated, and the concentrate was purified by silica gelthin layer chromatography (ethyl acetate:methanol=20:1) to give theobject compound (56 mg) described in the above-mentioned scheme.

Step 1-3

Compound (56 mg) obtained in step 1-2 was dissolved in trifluoroaceticacid (1.0 mL), and the mixture was stood at room temperature for 1 hr.The reaction solution was concentrated, ethyl acetate was added and themixture was concentrated. Ethyl acetate, 4N hydrochloric acid/ethylacetate solution, and hexane were added to allow crystallization to givethe object compound (28 mg) described in the above-mentioned scheme.

¹H-NMR (DMSO-d₆) δ: 12.30 (br s, 1H), 8.64 (s, 1H), 7.66 (s, 1H),7.34-7.30 (m, 2H), 7.16-7.11 (m, 2H), 4.57 (d, 1H, J=13.5 Hz), 4.39 (dd,1H, J=13.5, 3.9 Hz), 4.19 (s, 2H), 4.12-4.10 (m 1H), 3.87-3.80 (m, 1H),3.53-3.44 (m, 2H), 3.27-3.22 (m, 1H), 3.20 (s, 3H), 1.18 (t, 3H, J=7.1Hz).

Example 2 Step 2-1

Under nitrogen, a solution of 1M lithiumbis(trimethylsilyl)amide-THF/ethylbenzene (100 mL) in THF (100 mL) wascooled to −70° C., and tert-butyl acetate (13.5 mL) was added dropwiseunder stirring. After stirring for 15 min, benzyloxyacetyl chloride(7.52 mL) was added dropwise. After stirring for 1 hr, 2N aqueoushydrochloric acid solution was added to the reaction mixture until itspH reached 3 and the mixture was allowed to warm to room temperature.The mixture was extracted with ethyl acetate, and the organic layer waswashed with 2N aqueous hydrochloric acid solution and saturated brine,dried over sodium sulfate and concentrated. The above operation wasrepeated, and the both were combined to give the object compound (40.3g) described in the above-mentioned scheme as a crude product.

Step 2-2

To a solution of the compound (38 g) obtained in step 2-1 in toluene (80mL) was added dimethylformamidedimethylacetal (38 mL), and the mixturewas stirred at 100° C. for 1 hr. The mixture was allowed to cool, andconcentrated, and the concentrate was purified by silica gel columnchromatography (ethyl acetate:hexane=1:2-ethyl acetate) to give theobject compound (11.3 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 7.66 (s, 1H), 7.40-7.13 (m, 5H), 4.60 (s, 2H), 4.42(s, 2H), 3.40-2.65 (m, 6H), 1.45 (s, 9H).

Step 2-3

Under nitrogen, a solution of 1M lithiumbis(trimethylsilyl)amide-THF/ethylbenzene (42.5 mL) in THF (150 mL) wascooled to −70° C., and a solution of the compound (11.3 g) obtained instep 2-2 in THF (50 mL) was added dropwise over 3 min under stirring.After stirring for 20 min, ethyl chloroglyoxylate (4.75 mL) was added atonce. After stirring for 25 min, saturated aqueous potassium hydrogensulfate solution and ethyl acetate were added and the mixture wasallowed to warm to room temperature. The organic layer was separated,washed with saturated brine, dried over sodium sulfate, andconcentrated. Toluene was added to the residue, and the mixture wasconcentrated once. Toluene (100 mL) and triethylamine (10 mL) were addedand the mixture was stirred at room temperature. One hour later, themixture was concentrated, and the concentrate was purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:6-1:3) to give the objectcompound (6.03 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.39 (s, 1H), 7.51-7.47 (m, 2H), 7.39-7.30 (m, 3H),5.32 (s, 2H), 4.34 (q, 2H, J=7.2 Hz), 1.57 (s, 9H), 1.31 (t, 3H, J=7.2Hz).

Step 2-4

To a solution of the compound (18.7 g) obtained in step 2-3 in ethylacetate (20 mL) was added 4N hydrochloric acid/ethyl acetate (200 mL)under stirring, and the mixture was stirred at room temperature for 1hr. To the reaction mixture was added hexane (1 L), the mixture wasstirred for a while, and the crystals were collected by filtration, anddried to give the object compound (11.1 g) described in theabove-mentioned scheme.

¹H-NMR (CDCl₃) δ: 13.03 (s, 1H), 8.80 (s, 1H), 7.47-7.43 (m, 2H),7.41-7.35 (m, 3H), 5.38 (s, 2H), 4.40 (q, 2H, J=7.2 Hz), 1.35 (t, 3H,J=7.2 Hz).

Step 2-5

To a solution of the compound (6 g) obtained in step 2-4 in toluene (80mL) were added oxalyl chloride (3.27 mL) and dimethylformamide (0.04 mL)under stirring, and the mixture was stirred at room temperature for 2hr. The reaction mixture was concentrated, chloroform (100 ml) and thecompound (5.22 g) obtained in Reference Example 3 were added, and themixture was stirred at room temperature overnight. 5% Aqueous potassiumhydrogen sulfate solution was added, and the mixture was extracted twicewith chloroform. The organic layer was washed with 5% aqueous potassiumhydrogen sulfate solution and saturated brine, dried over magnesiumsulfate, and concentrated. The concentrate was purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:4-1:3), ethylacetate/hexane (1:3) solution was added, and the mixture was slurrywashed. The residue was collected by filtration, and dried to give theobject compound (6.348 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 9.07 (s, 1H), 7.49-7.44 (m, 2H), 7.39-7.28 (m, 5H),7.07-7.00 (m, 2H), 5.35 (s, 2H), 4.46 (s, 2H), 4.39 (q, 2H, J=7.1 Hz),1.34 (t, 3H, J=7.1 Hz).

Step 2-6

To a solution of(R)-2-tert-butoxycarbonylamino-3-hydroxy-2-methylpropionic acid (5.00 g)in dimethylformamide (50 mL) were added potassium carbonate (6.31 g) andiodomethane (2.84 mL), and the mixture was stirred at room temperaturefor 3 hr. Water (100 mL) was added, and the mixture was extracted withethyl acetate (150 mL). The organic layer was washed with saturatedaqueous sodium hydrogen carbonate solution (100 mL), dried andconcentrated to give the object compound (5.06 g) described in theabove-mentioned scheme.

¹H-NMR (CDCl₃) δ: 5.29 (br s, 1H), 3.99 (dd, 1H, J=11.6, 6.0 Hz),3.83-3.73 (m, 1H), 3.78 (s, 3H), 3.23 (br s, 1H), 1.48 (s, 3H), 1.45 (s,9H).

Step 2-7

To a solution of the compound (2.50 g) obtained in step 2-6 in dimethylsulfoxide (25 mL) were added triethylamine (2.25 mL) and apyridine-sulfur trioxide complex (2.62 g), and the mixture was stirredat room temperature for 1 hr. 1N Aqueous hydrochloric acid solution (100mL) was added, and the mixture was extracted with ethyl acetate (200mL). The organic layer was washed successively with 1N aqueoushydrochloric acid solution (100 mL) and saturated aqueous sodiumhydrogen carbonate solution (100 mL), dried and concentrated to give theobject compound (1.22 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 9.57 (s, 1H), 5.63 (br s, 1H), 3.81 (s, 3H), 1.57 (s,3H), 1.45 (s, 9H).

Step 2-8

To a solution of the compound (660 mg) obtained in step 2-7 inchloroform (7.0 mL) were added isopropylamine (368 μL), acetic acid (245μL) and sodium triacetoxyborohydride (955 mg), and the mixture wasstirred at room temperature for 18 hr. Saturated aqueous sodium hydrogencarbonate solution (30 mL) and chloroform (50 mL) were added and themixture was partitioned. The organic layer was washed with saturatedaqueous sodium hydrogen carbonate solution (30 mL), dried andconcentrated. The concentrate was purified by silica gel columnchromatography (chloroform:methanol=10:1) to give the object compound(764 mg) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 5.74 (br s, 1H), 3.74 (s, 3H), 2.89 (br s, 2H), 2.73(sep, 1H, J=6.2 Hz), 1.52 (s, 3H), 1.44 (s, 9H), 1.02 (d, 3H, J=6.2 Hz),1.02 (d, 3H, J=6.2 Hz).

Step 2-9

The compound (155 mg) obtained in step 2-8 was dissolved intrifluoroacetic acid solution (1.0 mL), and the mixture was stirred atroom temperature for 30 min. The mixture was concentrated, chloroformwas added, and the mixture was 25 concentrated. This operation wasperformed twice. Toluene (5 mL), diisopropylethylamine (395 μL) and thecompound (200 mg) obtained in step 2-5 were added, and the mixture wasstirred at room temperature for 30 min. Toluene (5 mL) and1,8-diazabicyclo[5.4.0]undec-7-ene (100 μL) were added, and the mixturewas stirred at 120° C. for 1 hr. The reaction mixture was allowed tocool to room temperature, acetic acid (1.0 mL) was added, and themixture was further stirred at 110° C. for 1 hr. 2N Aqueous hydrochloricacid solution (30 mL) was added, and the mixture was extracted withethyl acetate (60 mL). The organic layer was dried and concentrated,toluene was added, and this operation was repeated twice to give theobject compound (263 mg) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.87 (s, 1H), 7.59 (d, 2H, J=7.0 Hz), 7.41-7.13 (m,4H), 7.08-6.98 (m, 3H), 5.46 (d, 1H, J=10.0 Hz), 5.23 (d, 1H, J=10.0Hz), 4.86 (sep, 1H, J=6.3 Hz), 4.44 (s, 2H), 3.85 (d, 1H, J=13.5 Hz),3.44 (d, 1H, J=13.5 Hz), 1.96 (s, 3H), 1.14 (d, 3H, J=6.3 Hz), 1.12 (d,3H, J=6.3 Hz).

Step 2-10

To a solution of the compound (40.0 mg) obtained in step 2-9,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28.0 mg)and 1-hydroxybenzotriazole hydrate (22.0 mg) in dimethylformamide (400μL) was added azetidine (20 μL), and the mixture was stirred at roomtemperature for 18 hr. Saturated aqueous sodium hydrogen carbonatesolution (10 mL) was added, and the mixture was extracted with ethylacetate (25 mL). The organic layer was washed successively with 1Naqueous hydrochloric acid solution (10 mL) and saturated aqueous sodiumhydrogen carbonate solution (10 mL), dried and concentrated. Theconcentrate was purified by silica gel thin layer chromatography(chloroform:methanol=15:1) to give the object compound (26.7 mg)described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.99 (s, 1H), 7.64-7.58 (m, 2H), 7.36-7.27 (m, 5H),7.07-6.99 (m, 2H), 5.53 (d, 1H, J=10.0 Hz), 5.39 (d, 1H, J=10.0 Hz),4.82 (sep, 1H, J=6.7 Hz), 4.46 (s, 2H), 4.10-3.92 (m, 2H), 3.97 (d, 1H,J=13.4 Hz), 3.75-3.66 (m, 1H), 3.61-3.51 (m, 1H), 3.27 (d, 1H, J=13.4Hz), 2.19-2.05 (m, 2H), 1.97 (s, 3H), 1.15 (d, 6H, J=6.7 Hz).

Step 2-11

The compound (25.0 mg) obtained in step 2-10 was dissolved intrifluoroacetic acid (1.0 mL), and the mixture was stirred at roomtemperature for 30 min. The reaction solution was concentrated,chloroform was added, and the mixture was concentrated. 4N Hydrochloricacid/ethyl acetate solution was added, and the mixture was concentrated.Crystallization from ethyl acetate-hexane gave the object compound (17.2mg) described in the above-mentioned scheme.

¹H-NMR (DMSO-d₆) δ: 12.91 (br s, 1H), 8.71 (s, 1H), 7.46-7.38 (m, 2H),7.23-7.15 (m, 2H), 4.70 (sep, 1H, J=6.7 Hz), 4.48 (s, 2H), 4.29-4.18 (brm, 1H), 4.02 (d, 1H, J=13.9 Hz), 3.90-3.81 (br m, 2H), 3.80-3.72 (br m,1H), 3.71 (d, 1H, J=13.9 Hz), 2.16-2.04 (br m, 2H), 1.99 (s, 3H), 1.16(d, 3H, J=6.7 Hz), 1.14 (d, 3H, J=6.7 Hz).

Example 3 Step 3-1

To a solution of (R)-1-benzyloxymethyl-2-hydroxyethylcarbamic acidtert-butyl ester (5.0 g) and 2,6-di-tert-butylpyridine (8.0 mL) inchloroform (50 mL) were added iodomethane (1.33 mL) and silver(I)trifluoromethanesulfonate (6.85 g) under ice-cooling, and the mixturewas stirred for 30 min, and further stirred at room temperature for 1hr. The reaction suspension was filtered through celite, andconcentrated, and the concentrate was purified by silica gel columnchromatography (ethyl acetate:hexane=1:20-1:4) to give the objectcompound (2.8 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 7.38-7.27 (m, 5H), 4.97-4.85 (m, 1H), 4.53 (s, 15 2H),4.00-3.81 (m, 1H), 3.59 (dd, 1H, J=9.4, 4.2 Hz), 3.51 (dd, 1H, J=9.4,5.8 Hz), 3.51 (dd, 1H, J=9.4, 4.4 Hz), 3.44 (dd, 1H, J=9.4, 6.0 Hz),3.34 (s, 3H), 1.44 (s, 9H).

Step 3-2

To a solution of the compound (2.8 g) obtained in step 3-1 in methanol(100 mL) was added a 7.5% palladium-carbon catalyst (1.4 g), and themixture was stirred at room temperature for 17 hr under a hydrogenatmosphere and moderate pressure (0.4 MPa). The reaction mixture wasfiltered through celite and concentrated to give the object compound(2.05 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 5.22-5.10 (m, 1H), 3.84-3.64 (m, 3H), 3.60-3.49 (m,2H), 3.37 (s, 3H), 2.73-2.55 (m, 1H), 1.45 (s, 9H).

Step 3-3

To a solution of the compound (1.6 g) obtained in step 3-2, phthalimide(1.38 g) and triphenylphosphine (2.47 g) in tetrahydrofuran (20 mL) wasadded dropwise 2.2M diethyl azodicarboxylate/toluene solution (4.3 mL)under ice-cooling, and the mixture was stirred at room temperature for20 min. The reaction mixture was concentrated, and the concentrate waspurified by silica gel column chromatography (ethylacetate:hexane=1:10-1:2). The obtained solid was dissolved in ethanol(30 mL)-toluene (30 mL), hydrazine monohydrate (1.6 mL) was added, andthe mixture was stirred at 80° C. for 40 min. The mixture was allowed tocool to room temperature, the solid was filtered off, and the filtratewas concentrated. Toluene was added to the residue, and the precipitatedsolid was filtered off. The filtrate was concentrated to give the objectcompound (1.3 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 5.08-4.89 (m, 1H), 3.71-3.63 (m, 1H), 3.50 (dd, 1H,J=9.5, 3.7 Hz), 3.40 (dd, 1H, J=9.5, 5.1 Hz), 3.35 (s, 3H), 2.84 (dd,1H, J=13.0, 6.0 Hz), 2.80 (dd, 1H, 25 J=13.0, 6.0 Hz), 1.45 (s, 9H).

Step 3-4

To a solution of the compound (0.8 g) obtained in step 3-3 in dioxane (8mL) was added saturated aqueous sodium hydrogen carbonate solution (2mL), benzyl chloroformate (0.84 mL) was added dropwise underice-cooling, and the mixture was stirred for 40 min, and at roomtemperature for 10 min. Water (15 mL) was added, and the mixture wasextracted with ethyl acetate. The extract was dried, and concentrated,and the concentrate was purified by silica gel column chromatography(ethyl acetate:hexane=1:10-1:2). To the obtained solid was added 4Nhydrochloric acid/dioxane solution (5 mL), and the mixture was stirredat room temperature for 30 min. The reaction mixture was concentrated,and the residue was dissolved in chloroform. Saturated aqueous sodiumhydrogen carbonate solution (2 mL) was added, and the mixture wasstirred. The mixture was extracted with chloroform, and the organiclayer was dried and concentrated to give the object compound (639 mg)described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 7.39-7.28 (m, 5H), 5.27-5.20 (m, 1H), 5.10 (s, 2H),3.41-3.24 (m, 3H), 3.35 (s, 3H), 3.18-3.01 (m, 2H), 1.39 (br s, 2H).

Step 3-5

To a solution of the compound (150 mg) obtained in step 3-4 inchloroform (4 mL) were added acetone (70 μL), acetic acid (54 μL) andsodium triacetoxyborohydride (200 mg) under ice-cooling, and the mixturewas stirred at room temperature overnight. The reaction mixture wasdiluted with chloroform, saturated aqueous sodium hydrogen carbonatesolution was added, and the mixture was stirred. The chloroform layerwas washed with saturated brine, dried, and concentrated to give theobject compound (156 mg) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 7.39-7.28 (m, 5H), 5.39-5.29 (m, 1H), 5.10 (s, 2H),3.42-3.28 (m, 3H), 3.33 (s, 3H), 3.22-3.14 (m, 1H), 2.96-2.82 (m, 2H),1.04 (d, 3H, J=6.8 Hz), 1.02 (d, 3H, J=6.8 Hz).

Step 3-6

In the same manner as in step 2-9 and step 2-11, the object compound(17.0 mg) described in the above-mentioned scheme was obtained from thecompound (156 mg) obtained in step 3-5. For removal of theamino-protecting group (benzyloxycarbonyl group) of the compoundobtained in step 3-5, a known method was used according to theprotecting group.

¹H-NMR (DMSO-d₆) δ: 8.84 (s, 1H), 7.43-7.38 (m, 2H), 7.21-7.14 (m, 2H),4.66 (d, 1H, J=13.2 Hz), 4.47 (sep, 1H, J=6.7 Hz), 4.47 (s, 2H), 4.34(dd, 1H, J=13.5, 3.7 Hz), 4.22-4.17 (m, 1H), 3.49 (dd, 1H, J=10.6, 4.3Hz), 3.39 (dd, 1H, J=10.6, 7.5 Hz), 3.21 (s, 3H), 1.30 (d, 3H, J=6.7Hz), 1.28 (d, 3H, J=6.7 Hz).

Example 4 Step 4-1

To a solution of (R)-1-aminomethyl-2-methoxyethylcarbamic acidtert-butyl ester (1.0 g) produced from(S)-1-benzyloxymethyl-2-hydroxyethylcarbamic acid tert-butyl ester inthe same manner as in Example 3, step 3-1 to step 3-3 in chloroform (15mL) were added acetone (432 μL) and acetic acid (337 μL) underice-cooling, sodium triacetoxyborohydride (1.25 g) was added at roomtemperature, and the mixture was stirred at room temperature for 14 hr.To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted 3 times withchloroform. The combined chloroform layer was dried, and concentrated,and the concentrate was purified by silica gel column chromatography(chloroform:methanol=50:1-7:1) to give the object compound (1.12 g)described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 5.09-4.90 (m, 1H), 3.81-3.69 (m, 1H), 3.49 (dd, 1H,J=9.5, 4.0 Hz), 3.43-3.37 (m, 1H), 3.34 (s, 3H), 2.82-2.68 (m, 3H), 1.45(s, 9H), 1.04 (d, 3H, J=6.4 Hz), 1.03 (d, 3H, J=6.4 Hz).

Step 4-2

In the same manner as in step 2-9 and step 2-11 (known deprotection andcondensation reactions may be omitted as necessary), the object compound(10.8 mg) described in the above-mentioned scheme was obtained from thecompound (19.0 mg) obtained in step 4-1.

¹H-NMR (DMSO-d₆) δ: 12.82 (br s, 1H), 8.80 (s, 1H), 7.45-7.38 (m, 2H),7.23-7.15 (m, 2H), 5.01-4.93 (m, 1H), 4.77 (sep, 1H, J=6.7 Hz), 4.47 (s,2H), 3.84 (dd, 1H, J=13.8, 4.1 Hz), 3.75 (dd, 1H, J=13.8, 1.3 Hz),3.65-3.54 (m, 2H), 3.25 (s, 3H), 1.16 (d, 3H, J=6.7 Hz), 1.16 (d, 3H,J=6.7 Hz).

Example 5 Step 5-1

In the same manner as in step 3-3, the object compound (1.0 g) describedin the above-mentioned scheme was obtained from(S)-2-hydroxy-1-methylethylcarbamic acid tert-butyl ester (1.4 g).

¹H-NMR (CDCl₃) δ: 4.68-4.49 (m, 1H), 3.71-3.58 (m, 1H), 2.74 (dd, 1H,J=13.0, 4.9 Hz), 2.62 (dd, 1H, J=13.0, 6.5 Hz), 1.45 (s, 9H), 1.12 (d,3H, J=6.7 Hz).

Step 5-2

In the same manner as in step 4-1, the object compound (180 mg)described in the above-mentioned scheme was obtained from the compound(190 mg) obtained in step 5-1.

¹H-NMR (CDCl₃) δ: 4.91-4.66 (m, 1H), 3.81-3.66 (m, 1H), 2.81 (sep, 1H,J=6.4 Hz), 2.66 (dd, 1H, J=12.0, 4.9 Hz), 2.60 (dd, 1H, J=12.0, 6.7 Hz),1.45 (s, 9H), 1.14 (d, 3H, J=6.6 Hz), 1.06 (d, 6H, J=6.4 Hz).

Step 5-3

In the same manner as in step 2-9 and step 2-11, the object compound(27.5 mg) described in the above-mentioned scheme was obtained from thecompound (30.0 mg) obtained in step 5-2.

¹H-NMR (DMSO-d₆) δ: 12.81 (br s, 1H), 8.91 (s, 1H), 7.45-7.38 (m, 2H),7.22-7.15 (m, 2H), 4.92 (ddd, 1H, J=6.8, 3.5, 2.2 Hz), 4.80 (t, 1H,J=6.8 Hz), 4.47 (s, 2H), 3.81 (dd, 1H, J=13.5, 3.5 Hz), 3.63 (dd, 1H,J=13.5, 2.2 Hz), 1.39 (d, 3H, J=6.8 Hz), 1.19 (d, 3H, J=6.8 Hz), 1.16(d, 3H, J=6.8 Hz).

Example 6 Step 6-1

In the same manner as in step 3-3 to step 3-5, the object compound (105mg) described in the above-mentioned scheme was obtained from(R)-2-hydroxy-1-methylethylcarbamic acid tert-butyl ester (2.0 g).

¹H-NMR (CDCl₃) δ: 7.40-7.28 (m, 5H), 5.28 (br s, 1H), 5.10 (s, 2H),3.29-3.17 (m, 1H), 3.02-2.92 (m, 1H), 2.92-2.80 (m, 2H), 1.04 (d, 6H,J=6.3 Hz), 0.99 (d, 3H, J=6.0 Hz).

Step 6-2

In the same manner as in step 2-9 and step 2-11 (known deprotection andcondensation reactions may be omitted as necessary), the object compound(16.6 mg) described in the above-mentioned scheme was obtained from thecompound (105 mg) obtained in step 6-1. For removal of theamino-protecting group (benzyloxycarbonyl group) of the compoundobtained in step 6-1, a known method was used according to theprotecting group.

¹H-NMR (DMSO-d₆) δ: 12.54 (br s, 1H), 8.85 (s, 1H), 7.44-7.38 (m, 2H),7.22-7.15 (m, 2H), 4.62-4.53 (m, 1H), 4.51-4.44 (m, 3H), 4.32 (dd, 1H,J=13.1, 3.4 Hz), 4.26-4.18 (m, 1H), 1.27 (d, 3H, J=6.7 Hz), 1.26 (d, 3H,J=6.7 Hz), 1.21 (d, 3H, J=6.5 Hz).

Example 7 Step 7-1

2-Amino-2-methyl-1,3-propanediol (20.0 g) was suspended intetrahydrofuran (400 mL), and di-tert-butyl dicarbonate (41.6 g) wasadded. The mixture was stirred at room temperature for 3 hr andconcentrated. Dimethylformamide (200 mL) was added to dissolve theconcentrate again, imidazole (13.0 g) and tert-butylchlorodimethylsilane(29.3 g) were added, and the mixture was stirred at room temperature for15 hr. Water (500 mL) was added, and the mixture was extracted withethyl acetate (800 mL). The organic layer was washed with water (400mL), dried, and concentrated. The concentrate was purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:10) to give the objectcompound (35.9 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 5.13 (br s, 1H), 4.00 (br s, 1H), 3.77 (d, 1H, J=9.7Hz), 3.70 (dd, 1H, J=11.4, 4.2 Hz), 3.61 (d, 1H, J=9.7 Hz), 3.55 (dd,1H, J=11.4, 8.4 Hz), 1.44 (s, 9H), 1.19 (s, 3H) , 0.90 (s, 9H) , 0.07(s, 6H).

Step 7-2

To a solution of the compound (15.5 g) obtained in step 7-1 in dimethylsulfoxide (120 mL) were added triethylamine (8.12 mL) and a sulfurtrioxide-pyridine complex (11.9 g), and the mixture was stirred at roomtemperature for 3 hr. 1N Aqueous hydrochloric acid solution (300 mL) wasadded, and the mixture was extracted with ethyl acetate (700 mL). Theorganic layer was washed successively with 1N aqueous hydrochloric acidsolution (150 mL) and saturated aqueous sodium hydrogen carbonatesolution (200 mL), dried, and concentrated. The concentrate was purifiedby silica gel column chromatography (ethyl acetate:hexane=1:20) to givethe object compound (11.0 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 9.49 (s, 1H), 5.29 (br s, 1H), 3.86-3.71 (br m, 2H),1.45 (s, 9H), 1.34 (s, 3H), 0.88 (s, 9H), 0.05 (s, 6H).

Step 7-3

To a solution of the compound (11.0 g) obtained in step 7-2 inchloroform (110 mL) were added isopropylamine (4.46 mL), acetic acid(2.97 mL) and sodium triacetoxyborohydride (11.6 g), and the mixture wasstirred at room temperature for 15 hr. The mixture was partitionedbetween saturated aqueous sodium hydrogen carbonate solution (150 mL)and chloroform (200 mL). The organic layer was washed twice withsaturated aqueous sodium hydrogen carbonate solution (100 mL), dried,and concentrated. The concentrate was purified by silica gel columnchromatography (chloroformmethanol=10:1) to give the object compound(14.1 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 5.43 (br s, 1H), 3.73 (d, 1H, J=9.6 Hz), 3.58 (d, 1H,J=9.6 Hz), 2.80-2.66 (m, 2H), 2.55 (d, 1H, J=11.6 Hz), 1.43 (s, 9H),1.24 (s, 3H), 1.05 (br s, 6H), 0.89 (s, 9H), 0.05 (s, 6H).

Step 7-4

To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (5.00 g)in toluene (100 mL) were added triethylamine (3.40 mL) and thionylchloride (1.78 mL) at 0° C., and the mixture was stirred at 0° C. for 30min. The precipitated salt was filtered off, the filtrate wasconcentrated, and the concentrate was dissolved in tetrahydrofuran (40mL). This tetrahydrofuran solution was added dropwise to a solution ofthe compound (10.3 g) obtained in step 7-3 and pyridine (30 mL) intetrahydrofuran (60 mL) at 0° C., and the mixture was stirred at roomtemperature for 30 min. The reaction mixture was concentrated, toluenewas added and the mixture was concentrated. This operation was performedtwice. 1N Aqueous hydrochloric acid solution (150 mL) was added, and themixture was extracted with ethyl acetate (250 mL). The organic layer waswashed with saturated aqueous sodium hydrogen carbonate solution (100mL), dried, and concentrated. The concentrate was purified by silica gelcolumn chromatography (chloroformmethanol=50:1) to give the objectcompound (9.65 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 7.74-7.66 (m, 1H), 7.46-7.28 (m, 5H), 6.50-6.42 (m,1H), 5.96 (br s, 1H), 5.28-5.14 (m, 2H), 4.02-3.33 (m, 5H), 1.47-1.37(m, 9H), 1.29-1.00 (m, 9H), 0.95-0.83 (m, 9H), 0.13-0.03 (m, 6H).

Step 7-5

To the compound (9.65 g) obtained in step 7-4 was added 4N hydrochloricacid/ethyl acetate solution (100 mL), and the mixture was stirred atroom temperature for 30 min. This was concentrated, ethanol (400 mL) andsaturated aqueous sodium hydrogen carbonate solution (100 mL) wereadded, and the mixture was stirred at room temperature for 18 hr. Theinsoluble material was filtered off, and the filtrate was concentrated.Water (100 mL) was added, and the mixture was extracted twice withchloroform (200 mL, 100 mL). The organic layer was dried, andconcentrated, and the concentrate was purified by silica gel columnchromatography (chloroform:methanol=30:1-20:1-10:1) to give the objectcompound (2.20 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 7.52 (d, 2H, J=7.9 Hz), 7.48 (d, 1H, J=7.9 Hz),7.37-7.22 (m, 3H), 6.25 (d, 1H, J=7.9 Hz), 5.79 (br s, 1H), 5.20 (d, 1H,J=10.0 Hz), 5.17 (d, 1H, J=10.0 Hz), 4.85 (sep, 1H, J=6.5 Hz), 3.80 (d,1H, J=12.1 Hz), 3.61 (d, 1H, J=12.1 Hz), 3.35 (d, 1H, J=14.2 Hz), 3.14(d, 1H, J=14.2 Hz), 1.47 (s, 3H), 1.12 (d, 3H, J=6.5 Hz), 1.11 (d, 3H,J=6.5 Hz).

Step 7-6

The compound (2.20 g) obtained in step 7-5, trimethylphenylammoniumtribromide (3.48 g) and sodium hydrogen carbonate (1.04 g) weredissolved in 2:1 chloroform-methanol (60 mL), and the mixture wasstirred at room temperature for 30 min. Saturated aqueous sodiumhydrogen carbonate solution (100 mL) was added, and the mixture wasextracted with chloroform (200 mL). The organic layer was washedsuccessively with 1N aqueous hydrochloric acid solution (100 mL) andsaturated aqueous sodium hydrogen carbonate solution (100 mL), dried,and concentrated to give the object compound (2.23 g) described in theabove-mentioned scheme.

¹H-NMR (DMSO-d₆) δ: 8.22 (s, 1H), 7.53 (d, 2H, J=7.0 Hz), 7.41-7.27 (m,3H), 5.48 (br s, 1H), 5.10 (d, 1H, J=10.2 Hz), 5.03 (d, 1H, J=10.2 Hz),4.67 (sep, 1H, J=6.7 Hz), 3.66 (d, 1H, J=11.6 Hz), 3.59 (d, 1H, J=11.6Hz), 3.56 (d, 1H, J=14.2 Hz), 3.45 (d, 1H, J=14.2 Hz), 1.48 (s, 3H),1.11 (d, 6H, J=6.7 Hz).

Step 7-7

To a solution of the compound (2.12 g) obtained in step 7-6 inchloroform (45 mL) were added 3,4-dihydro-2H-pyran (882 μL) andcamphorsulfonic acid (56 mg), and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was concentrated, and theconcentrate was purified by silica gel column chromatography(chloroform:methanol=30:1) to give the object compound (2.23 g)described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 7.91-7.89 (m, 1H), 7.72-7.66 (m, 2H), 7.37-7.27 (m,3H), 5.41-5.36 (m, 1H), 5.27-5.17 (m, 1H), 5.02-4.92 (m, 1H), 4.61-4.48(m, 1H), 3.92-3.81 (m, 1H), 3.79-3.27 (m, 5H), 1.78-1.48 (m, 9H),1.20-1.14 (m, 6H).

Step 7-8

The compound (250 mg) obtained in step 7-7,tris(dibenzylideneacetone)dipalladium (44 mg), tri(2-furyl)phosphine (45mg) and 5-(2,4-difluorobenzyl)-2-tributylstanylthiazole (835 mg) weredissolved in dioxane (5.0 mL), and the mixture was heated in a microwaveapparatus at 110° C. for 40 min. This operation was performed twiceusing the same amounts, and the reaction mixtures were combined andconcentrated. The concentrate was purified by silica gel columnchromatography (chloroform:methanol=30:1) to give the object compound(682 mg) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.78-8.74 (m, 1H), 7.72-7.67 (m, 2H), 7.60-7.56 (m,1H), 7.37-7.17 (m, 4H), 6.86-6.71 (m, 2H), 5.52-5.46 (m, 1H), 5.34-5.25(m, 1H), 5.03-4.93 (m, 1H), 4.62-4.53 (m, 1H), 4.20-4.14 (m, 2H),4.02-3.87 (m, 1H), 3.77-3.43 (m, 5H), 3.36-3.26 (m, 1H), 1.78-1.42 (m,8H), 1.21-1.13 (m, 6H).

Step 7-9

The compound (682 mg) obtained in step 7-8 was dissolved intetrahydrofuran-methanol-water (4:1:1, 6.0 mL). Acetic acid (2.0 mL) wasadded, and the mixture was stirred at 80° C. for 30 hr. The reactionmixture was concentrated, toluene was added, and the mixture wasconcentrated. This operation was performed twice, and the concentratewas purified by silica gel column chromatography(chloroformmethanol=40:1) to give the object compound (390 mg) describedin the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.66 (s, 1H), 7.67-7.62 (m, 2H), 7.51 (s, ¹H),7.36-7.25 (m, 3H), 7.24-7.15 (m, 1H), 6.84-6.75 (m, 2H), 5.40 (d, 1H,J=9.7 Hz), 5.29 (d, 1H, J=9.7 Hz), 4.93 (sep, 1H, J=6.7 Hz), 4.14 (s,2H), 3.86 (s, 2H), 3.51 (d, 1H, J=13.9 Hz), 3.25 (d, 1H, J=13.9 Hz),1.65 (s, 3H), 1.16 (d, 3H, J=6.7 Hz), 1.15 (d, 3H, J=6.7 Hz).

Step 7-10

To a solution of the compound (250 mg) obtained in step 7-9 inchloroform (5.0 mL) were added triethylamine (93 μL) and methanesulfonylchloride (41 μL) at 0° C., and the mixture was stirred at 0° C. for 1hr. Triethylamine (93 μL) and methanesulfonyl chloride (41 μL) wereadded, and the mixture was further stirred at 0° C. for 1 hr. Saturatedaqueous sodium hydrogen carbonate solution (20 mL) was added, and themixture was extracted with chloroform (40 mL). The organic layer waswashed with 1N aqueous hydrochloric acid solution (20 mL), dried, andconcentrated to give the object compound (295 mg) described in theabove-mentioned scheme.

¹H-NMR (CDCl₃) δ: 7.68-7.61 (m, 4H), 7.40-7.20 (m, 4H), 6.92-6.82 (m,2H), 5.45 (d, 1H, J=9.8 Hz), 5.32 (d, 1H, J=9.8 Hz), 4.98 (sep, 1H,J=6.8 Hz), 4.80 (br s, 1H), 4.50 (d, 1H, J=10.1 Hz), 4.19 (s, 2H), 3.58(d, 1H, J=14.1 Hz), 3.37 (d, 1H, J=14.1 Hz), 3.20 (br s, 3H), 1.85 (s,3H), 1.22 (d, 3H, J=6.8 Hz), 1.19 (d, 3H, J=6.8 Hz).

Step 7-11

The compound (30 mg) obtained in step 7-10 and potassium phthalimide (26mg) were dissolved in dimethylformamide (1.0 mL), and the mixture washeated in a microwave apparatus at 150° C. for 2 hr. This operation wasperformed two more times using the compound (115 mg) obtained in step7-10, potassium phthalimide (100 mg) and dimethylformamide (4.0 mL), andall the reaction mixtures were combined. Water (30 mL) was added, andthe mixture was extracted with ethyl acetate (60 mL). The organic layerwas washed successively with 1N aqueous hydrochloric acid solution (30mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL),dried and concentrated. The concentrate was purified by silica gelcolumn chromatography (chloroform:methanol=30:1) to give the objectcompound (277 mg) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.45 (s, 1H), 7.91-7.58 (m, 7H), 7.40-7.14 (m, 4H),6.85-6.76 (m, 2H), 5.60 (d, 1H, J=9.7 Hz), 5.31 (d, 1H, J=9.7 Hz), 5.07(sep, 1H, J=6.7 Hz), 4.21 (d, 1H, J=14.4 Hz), 4.12 (s, 2H), 3.88 (d, 1H,J=14.4 Hz), 3.58 (d, 1H, J=13.9 Hz), 3.47 (d, 1H, J=13.9 Hz), 1.78 (s,3H), 1.29 (d, 3H, J=6.7 Hz), 1.21 (d, 3H, J=6.7 Hz).

Step 7-12

To a solution of the compound (277 mg) obtained in step 7-11 in 1:1ethanol-toluene (6.0 mL) was added hydrazine monohydrate (60 μL), andthe mixture was stirred at 80° C. for 3 hr. Furthermore, hydrazinemonohydrate (60 μL) was added, and the mixture was stirred at 80° C. for2 hr. The precipitate was filtered off, and the filtrate wasconcentrated, and the concentrate was purified by silica gel columnchromatography (chloroform:methanol=30:1-20:1) to give the objectcompound (104 mg) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.71 (s, 1H), 7.71-7.63 (m, 2H), 7.59 (s, 1H),7.38-7.27 (m, 3H), 7.25-7.16 (m, 1H), 6.85-6.76 (m, 2H), 5.53 (d, 1H,J=9.7 Hz), 5.26 (d, 1H, J=9.7 Hz), 4.97 (sep, 1H, J=6.7 Hz), 4.18 (s,2H), 3.51 (d, 1H, J=13.9 Hz), 3.32 (d, 1H, J=13.9 Hz), 3.05 (d, 1H,J=13.7 Hz), 2.98 (d, 1H, J=13.7 Hz), 1.67 (s, 3H), 1.20 (d, 3H, J=6.7Hz), 1.18 (d, 3H, J=6.7 Hz).

Step 7-13

To a solution of the compound (20.0 mg) obtained in step 7-12 inchloroform (400 μL) were added triethylamine (9.9 μL) and propionylchloride (4.8 μL), and the mixture was stirred at room temperature for 1hr. The obtained reaction mixture was directly purified by silica gelthin layer chromatography (chloroform:methanol=10:1) to give the objectcompound (14.2 mg) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.58 (s, 1H), 7.64-7.59 (m, 2H), 7.52 (s, 1H),7.36-7.27 (m, 3H), 7.25-7.17 (m, 1H), 6.86-6.78 (m, 2H), 6.21 (br s,1H), 5.40 (d, 1H, J=9.7 Hz), 5.28 (d, 1H, J=9.7 Hz), 4.96 (sep, 1H,J=6.7 Hz), 4.15 (s, 2H), 3.76 (dd, 1H, J=14.7, 7.1 Hz), 3.55 (dd, 1H,J=14.7, 6.4 Hz), 3.39 (d, 1H, J=13.7 Hz), 3.35 (d, 1H, J=13.7 Hz), 2.28(dt, 2H, J=14.5, 6.6 Hz), 1.61 (s, 3H), 1.17 (d, 3H, J=6.7 Hz), 1.16 (d,3H, J=6.7 Hz), 1.14 (t, 3H, J=7.7 Hz).

Step 7-14

To a solution of the compound (14.0 mg) obtained in step 7-13 intetrahydrofuran (1.0 mL) were added excess amounts of iodomethane andpotassium tert-butoxide at 0° C. (until disappearance of startingmaterials). The obtained reaction mixture was directly purified bysilica gel thin layer chromatography (chloroform:methanol=15:1) to givethe object compound (5.6 mg) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.60 (s, 1H), 7.68-7.63 (m, 2H), 7.58 (s, 1H),7.36-7.27 (m, 3H), 7.25-7.19 (m, 1H), 6.86-6.77 (m, 2H), 5.58 (d, 1H,J=10.0 Hz), 5.32 (d, 1H, J=10.0 Hz), 4.98 (sep, 1H, J=6.7 Hz), 4.28 (d,1H, J=14.4 Hz), 4.19 (s, 2H), 3.47 (d, 1H, J=14.2 Hz), 3.32 (d, 1H,J=14.2 Hz), 3.12 (d, 1H, J=14.4 Hz), 2.54 (s, 3H), 2.37 (dq, 1H, J=15.5,7.0 Hz), 2.30 (dq, 1H, J=15.5, 7.0 Hz), 1.69 (s, 3H), 1.21 (d, 3H, J=6.7Hz), 1.17 (d, 3H, J=6.7 Hz), 1.15 (t, 3H, J=7.0 Hz).

Step 7-15

The compound (5.6 mg) obtained in step 7-14 was dissolved intrifluoroacetic acid (1.0 mL), and the mixture was stirred at roomtemperature for 1 hr. The reaction solution was concentrated, chloroformwas added, and the mixture was concentrated. 4N Hydrochloric acid/ethylacetate solution was added, and the mixture was concentrated.Crystallization from ethyl acetate-hexane gave the object compound (3.2mg) described in the above-mentioned scheme.

¹H-NMR (DMSO-d₆) δ: 13.18 (br s, 1H), 8.41 (s, 1H), 7.65 (s, 1H), 7.44(td, 1H, J=8.8, 6.7 Hz), 7.25 (ddd, 1H, J=10.2, 9.3, 2.6 Hz), 7.07 (tdd,1H, J=8.8, 2.6, 0.9 Hz), 4.80 (sep, 1H, J=6.7 Hz), 4.21 (s, 2H), 3.83(d, 1H, J=14.1 Hz), 3.78 (d, 1H, J=13.7 Hz), 3.68 (d, 1H, J=13.7 Hz),3.51 (d, 1H, J=14.1 Hz), 2.77 (s, 3H), 2.16-2.03 (m, 2H), 1.67 (s, 3H),1.22 (d, 3H, J=6.7 Hz), 1.17 (d, 3H, J=6.7 Hz), 0.69 (t, 3H, J=7.3 Hz).

Example 8 Step 8-1

Under nitrogen, a solution of 1.6M lithium hexamethyldisilazide-THF(11.73 mL) in THF (100 mL) was cooled to −78° C., and a solution of thecompound (5 g) obtained in step 2-2 in THF (15 mL) was added dropwiseover 2 min under stirring. After stirring for 13 min, tert-butylchloroglyoxylate (3.58 mL) was added at once. After stirring for 25 min,saturated aqueous potassium hydrogen sulfate solution and ethyl acetatewere added, and the mixture was allowed to warm to room temperature. Theorganic layer was separated, washed with saturated aqueous potassiumhydrogen sulfate solution and saturated brine, dried over sodiumsulfate, and concentrated. Toluene was added to the residue, and themixture was concentrated once. Toluene (100 mL) and triethylamine (10mL) were added and the mixture was stirred at room temperature, andconcentrated 30 min later. The above-mentioned operation was repeatedonce more, and the both were combined and purified by silica gel columnchromatography (ethyl acetate:hexane=1:9-1:6) to give the objectcompound (4.496 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.37 (s, 1H), 7.52-7.49 (m, 2H), 7.39-7.29 (m, 3H),5.27 (s, 2H), 1.57 (s, 9H), 1.51 (s, 9H).

Step 8-2

To a solution of the compound (4.49 g) obtained in step 8-1 in dioxane(5 mL) was added 4N hydrochloric acid/dioxane solution (20 mL) withstirring, and the mixture was stirred at room temperature for 20 min.The reaction mixture was concentrated, ethyl acetate/hexane (1:4)solution was added and the mixture was slurry washed. The residue wascollected by filtration, and dried to give the object compound (3.30 g)described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.78 (s, 1H), 7.48-7.44 (m, 2H), 7.41-7.34 (m, 3H),5.34 (s, 2H), 1.54 (s, 9H).

Step 8-3

To a solution of the compound (1 g) obtained in step 8-2 in toluene (20mL)/chloroform (5 mL) were added oxalyl chloride (0.326 mL) anddimethylformamide (0.01 mL) under stirring, and the mixture was stirredat room temperature for 30 min. The reaction mixture was concentrated,THF (20 mL) was added, and the mixture was cooled to −78° C. undernitrogen. Triethylamine (1.21 mL) and (2,4-difluorophenyl)thioaceticacid hydrazide (555 mg) were added, and the temperature of the mixturewas raised slowly. After 25 min, ethyl acetate and water were added, andthe mixture was warmed to room temperature. The mixture was extractedtwice with ethyl acetate, and the organic layer was washed withsaturated brine, dried over sodium sulfate, and concentrated. To theresidue was added acetic acid (20 mL), and the mixture was stirred at100° C. for 2 hr. The mixture was allowed to cool to room temperature,and concentrated. The concentrate was purified by silica gel columnchromatography (ethyl acetate:hexane=1:9-1:4) to give the objectcompound (112 mg) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 9.05 (s, 1H), 7.50-7.46 (m, 1H), 7.39-7.18 (m, 5H),6.91-6.80 (m, 2H), 5.32 (s, 2H), 4.49 (s, 2H), 1.53 (s, 9H)

Step 8-4

A solution of the compound (1.01 g) obtained in step 8-3 in formic acid(20 mL) was stirred at room temperature for 2 hr. The reaction mixturewas concentrated, ethyl acetate/hexane (1:4) solution was added and themixture was slurry washed. The crystals were collected by filtration.The mother liquor was concentrated, formic acid (20 mL) was added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated, ethyl acetate/hexane (1:4) solution was addedand the mixture was slurry washed. The crystals were collected byfiltration. The both crystals were combined and dried to give the objectcompound (238 mg) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 9.13 (s, 1H), 7.43-7.18 (m, 6H), 6.93-6.79 (m, 2H),5.67 (s, 2H), 4.51 (s, 2H).

Step 8-5

To a solution of the compound (69 mg) obtained in step 8-4 inN,N-dimethylformamide (1.5 mL) were addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (86 mg), 1-hydroxy-7-azabenzotriazole (HOAt)(31 mg), triethylamine (1.1 mL) and[4-(isopropylaminomethyl)tetrahydropyran-4-yl]carbamic acid tert-butylester (49 mg) under ice-cooling, and the mixture was stirred at roomtemperature overnight. To the reaction mixture was added 5% aqueouspotassium hydrogen sulfate solution, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated aqueoussodium hydrogen carbonate solution, dried, and concentrated. Theconcentrate was purified by silica gel thin layer chromatography(chloroform:methanol=10:1) to give the object compound (18 mg) describedin the above-mentioned scheme.

Step 8-6

To the compound (18 mg) obtained in step 8-5 was added 4N hydrochloricacid/dioxane solution (1 mL), and the mixture was left standing at roomtemperature for 1.5 hr. The reaction mixture was concentrated,2-propanol (6 mL), water (0.6 mL) and saturated aqueous sodium hydrogencarbonate solution (0.6 mL) were added, and the mixture was stirred withheating at 100° C. for 4 hr. The mixture was allowed to cool to roomtemperature once, left standing overnight, and stirred again withheating at 100° C. for 8 hr. To the reaction mixture was added saturatedbrine, and the mixture was extracted with ethyl acetate, dried andconcentrated. The concentrate was purified by silica gel thin layerchromatography (chloroform:methanol=10:1) to give the object compound(10 mg) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 9.05 (s, 1H), 7.66-7.62 (m, 2H), 7.38-7.28 (m, 4H),6.88-6.81 (m, 2H), 5.38 (s, 2H), 4.97 (sep, 1H, J=7.0 Hz), 4.47 (s, 2H),4.11-4.04 (m, 2H), 3.74-3.65 (m, 2H), 3.55 (s, 2H), 2.45-2.36 (m, 2H),2.01-1.94 (m, 2H), 1.22 (d, 6H, J=7.0 Hz).

Step 8-7

The compound (10 mg) obtained in step 8-6 was dissolved intrifluoroacetic acid (1.0 mL), and the mixture was stood at roomtemperature for 50 min. Trifluoroacetic acid solution was concentrated,4N hydrochloric acid/dioxane solution was added and the mixture wasconcentrated. Toluene was added and the mixture was concentrated. Theobtained residue was crystallized from ethyl acetate (0.5 mL)-hexane (2mL) to give the object compound (4.7 mg) described in theabove-mentioned scheme.

¹H-NMR (DMSO-dd 5: 13.25 (br s, 1H), 8.88 (s, 1H), 7.58-7.50 (m, 1H),7.32-7.25 (m, 1H), 7.15-7.09 (m, 1H), 4.83 (sep, 1H, J=6.9 Hz), 4.50 (s,2H), 3.89-3.82 (m, 2H), 3.88 (br s, 2H), 3.80-3.73 (m, 2H), 2.31-2.22(m, 2H), 2.01-1.94 (m, 2H), 1.23 (d, 6H, J=6.9 Hz).

Example 9

In the same manner as in step 2-9 (amino-protecting group was removed bya known method according to the protecting group) and step 2-11, theobject compound (18.0 mg) described in the above-mentioned scheme wasobtained from ((S)-2-ethylamino-3-methoxypropyl)carbamic acid benzylester (80 mg) obtainable from a commercially available compound by aknown method.

¹H-NMR (DMSO-d₆) δ: 12.64-12.34 (m, 1H), 8.83 (s, 1H), 7.44-7.37 (m,2H), 7.22-7.14 (m, 2H), 4.64 (dd, 1H, J=13.4, 1.5 Hz), 4.47 (s, 2H),4.42 (dd, 1H, J=13.4, 4.4 Hz), 4.17-4.11 (m, 1H), 3.86 (dq, 1H, J=14.0,7.0 Hz), 3.54 (dd, 1H, J=10.4, 4.9 Hz), 3.50 (dd, 1H, J=10.4, 6.3 Hz),3.27 (dq, 1H, J=14.0, 7.0 Hz), 3.22 (s, 3H), 1.20 (t, 3H, J=7.0 Hz).

Example 10

In the same manner as in step 2-9 (amino-protecting group was removed bya known method according to the protecting group) and step 2-11, theobject compound (10.7 mg) described in the above-mentioned scheme wasobtained from ((S)-2-cyclopropylmethylamino-3-methoxypropyl)carbamicacid benzyl ester (36 mg) obtainable from a commercially availablecompound by a known method.

¹H-NMR (DMSO-d₆) δ: 12.46 (br s, 1H), 8.85 (s, 1H), 7.44-7.38 (m, 2H),7.22-7.15 (m, 2H), 4.67 (dd, 1H, J=13.7, 1.6 Hz), 4.47 (s, 2H), 4.45(dd, 1H, J=13.7, 3.9 Hz), 4.27-4.20 (m, 1H), 3.69 (dd, 1H, J=14.0, 7.0Hz), 3.58 (dd, 1H, J=10.3, 4.8 Hz), 3.51 (dd, 1H, J=10.3, 6.5 Hz), 3.21(dd, 1H, J=14.0, 7.0 Hz), 3.21 (s, 3H), 1.21-1.10 (m, 1H), 0.59-0.47 (m,2H), 0.44-0.36 (m, 1H), 0.36-0.27 (m, 1H).

Example 11

In the same manner as in step 2-9 (amino-protecting group was removed bya known method according to the protecting group) and step 2-11, theobject compound (32.0 mg) described in the above-mentioned scheme wasobtained from ((S)-2-cyclopropylmethylamino-3-ethoxypropyl)carbamic acidbenzyl ester (295 mg) obtainable from a commercially available compoundby a known method.

¹H-NMR (DMSO-d₆) δ: 12.50 (br s, 1H), 8.84 (s, 1H), 7.43-7.38 (m, 2H),7.21-7.15 (m, 2H), 4.67 (d, 1H, J=12.3 Hz), 4.46 (s, 2H), 4.46-4.42 (m,1H), 4.22-4.19 (m, 2H), 3.67 (dd, 1H, J=14.2, 7.2 Hz), 3.61 (dd, 1H,J=10.4, 4.4 Hz), 3.55 (dd, 1H, J=10.4, 6.2 Hz), 3.40-3.32 (m, 2H), 3.21(dd, 1H, J=14.2, 7.0 Hz), 0.94 (t, 3H, J=7.0 Hz), 0.54-0.46 (m, 2H),0.41-0.37 (m, 1H), 0.33-0.27 (m, 1H).

Example 12

In the same manner as in step 2-9 (amino-protecting group was removed bya known method according to the protecting group) and step 2-11, theobject compound (35.0 mg) described in the above-mentioned scheme wasobtained from ((S)-3-ethoxy-2-isopropylaminopropyl)carbamic acid benzylester (230 mg) obtainable from a commercially available compound by aknown method.

¹H-NMR (DMSO-d₆) δ: 12.40 (br s, 1H), 8.85 (s, 1H), 7.43-7.40 (m, 2H),7.22-7.16 (m, 2H), 4.67, (d, 1H, J=11.9 Hz), 4.51-4.47 (m, 1H), 4.47 (s,2H), 4.35 (dd, 1H, J=13.3, 3.9 Hz), 4.20-4.16 (m, 1H), 3.54 (dd, 1H,J=10.5, 4.1 Hz), 3.45-3.32 (m, 3H), 1.30 (d, 3H, J=4.6 Hz), 1.28 (d, 3H,J=4.6 Hz), 0.96 (t, 3H, J=7.0 Hz).

Example 13

In the same manner as in step 2-9 (amino-protecting group was removed bya known method according to the protecting group) and step 2-11, theobject compound (37.0 mg) described in the above-mentioned scheme wasobtained from ((S)-3-ethoxy-2-ethylaminopropyl)carbamic acid benzylester (250 mg) obtainable from a commercially available compound by aknown method.

¹H-NMR (DMSO-d₆) δ: 12.50 (br s, 1H), 8.84 (s, 1H), 7.43-7.40 (m, 2H),7.22-7.16 (m, 2H), 4.67, (dd, 1H, J=13.5, 1.5 Hz), 4.47 (s, 2H), 4.35(dd, 1H, J=13.5, 4.2 Hz), 4.14-4.11 (m, 1H), 3.91-3.82 (m, 1H),3.60-3.53 (m, 2H), 3.41-3.34 (m, 2H), 3.31-3.23 (m, 1H), 1.20 (t, 3H,J=7.2 Hz), 0.96 (t, 3H, J=7.0 Hz).

Example 14

In the same manner as in step 2-9 (amino-protecting group was removed bya known method according to the protecting group) and step 2-11, theobject compound (32.9 mg) described in the above-mentioned scheme wasobtained from ((1S,2S)-2-ethylamino-3-methoxy-1-methylpropyl)carbamicacid benzyl ester (51 mg) obtainable from a commercially availablecompound by a known method.

¹H-NMR (DMSO-d₆) δ: 12.77 (br s, 1H), 8.62 (s, 1H), 7.42-7.38 (m, 2H),7.20-7.16 (m, 2H), 4.77-4.71 (m, 1H), 4.47 (s, 2H), 4.14 (q, 1H, J=4.0Hz), 3.92-3.84 (m, 1H), 3.59 (d, 2H, J=4.4 Hz), 3.33-3.26 (m, 1H), 3.18(s, 3H), 1.64 (d, 3H, J=6.5 Hz), 1.21 (t, 3H, J=7.1 Hz).

Example 15

In the same manner as in step 2-9 and step 2-11, the object compound(6.2 mg) described in the above-mentioned scheme was obtained from[(R)-2-isopropylamino-1-((2-methoxyethoxy)methyl)ethyl]carbamic acidtert-butyl ester (19.3 mg) obtainable from a commercially availablecompound by a known method.

¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8.82 (s, 1H), 7.45-7.38 (m, 2H),7.23-7.15 (m, 2H), 4.99-4.91 (m, 1H), 4.77 (sep, 1H, J=6.7 Hz), 4.47 (s,2H), 3.84 (dd, 1H, J=13.8, 4.1 Hz), 20 3.78-3.68 (m, 2H), 3.64 (dd, 1H,J=10.4, 7.7 Hz), 3.58-3.45 (m, 2H), 3.34 (t, 2H, J=4.5 Hz), 3.11 (s,3H), 1.17 (d, 3H, J=6.7 Hz), 1.16 (d, 3H, J=6.7 Hz).

Example 16

In the same manner as in step 2-9 and step 2-11, the object compound(10.7 mg) described in the above-mentioned scheme was obtained from[(R)-2-cyclopropylamino-1-((2-methoxyethoxy)methyl)ethyl]carbamic acidtert-butyl ester (16 mg) obtainable from a commercially availablecompound by a known method.

¹H-NMR (DMSO-d₆) δ: 8.81 (s, 1H), 7.45-7.37 (m, 2H), 7.22-7.14 (m, 2H),4.92-4.84 (br m, 1H), 4.47 (s, 2H), 4.09-3.99 (m, 1H), 3.74-3.57 (m,3H), 3.56-3.44 (m, 2H), 3.34 (t, 2H, J=4.6 Hz), 3.13 (s, 3H), 2.94-2.84(m, 1H), 0.97-0.67 (m, 4H).

Example 17

In the same manner as in step 2-9 to step 2-11, the object compound (39mg) described in the above-mentioned scheme was obtained from(R)-2-tert-butoxycarbonylamino-3-ethylamino-2-methylpropionic acidmethyl ester (60 mg) obtainable from a commercially available compoundby a known method.

¹H-NMR (DMSO-d₆) δ: 12.69 (m, 1H), 8.60 (s, 1H), 7.69 (s, 1H), 7.34-7.30(m, 2H), 7.16-7.12 (m, 2H), 4.20 (s, 2H), 4.18-4.13 (m, 1H), 4.01 (d,1H, J=13.5 Hz), 3.89 (d, 1H, J=13.5 Hz), 3.87-3.80 (m, 2H), 3.67-3.61(m, 1H), 3.54-3.44 (m, 2H), 2.12-2.04 (m, 2H), 1.91 (s, 3H), 1.10 (t,3H, J=7.2 Hz).

Example 340 Step 340-1

To a solution of L-threoninol (2.05 g) in chloroform (14 mL) were addeddi-tert-butyl dicarbonate (4.26 g) and saturated aqueous sodium hydrogencarbonate solution (10 mL) and the mixture was stirred at roomtemperature for 3 hr and left standing for 3 days. To the reactionmixture was added saturated brine, and the mixture was extracted withchloroform. The organic layer was dried, and concentrated. The obtainedresidue was dissolved in dimethylformamide (40 mL) and, underice-cooling, imidazole (2.97 g) and tert-butylchlorodimethylsilane (1.49g) were added, and the mixture was stirred at room temperature for 45min. Water was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried, andconcentrated. The concentrate was purified by silica gel columnchromatography (ethyl acetate:hexane=1:10-1:3) to give the objectcompound (2.39 g) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 5.18 (d, 1H, J=8.2 Hz), 4.18-4.14 (m, 1H), 3.89 (dd,1H, J=10.4, 3.3 Hz), 3.82 (dd, 1H, J=10.4, 2.6 Hz), 3.48-3.45 (m, 1H),3.29 (s, 1H), 1.46 (s, 9H), 1.18 (d, 3H, J=6.2 Hz), 0.90 (s, 9H), 0.08(s, 6H).

Step 340-2

To a solution of the compound (2.39 g) obtained in step 340-1 in toluene(12 mL) were added tetrabutylammonium hydrogen sulfate (76 mg), 50%aqueous sodium hydroxide solution (8 mL) and methyl sulfate (922 μL)under ice-cooling, and the mixture was stirred at room temperature for90 min. Ice water was added, and the mixture was extracted with toluene.The organic layer was washed with saturated brine, dried, andconcentrated. The obtained residue was dissolved in tetrahydrofuran (20mL), 1.0M tetrabutylammonium fluoride/tetrahydrofuran solution (8.16 mL)was added and the mixture was stirred at room temperature for 100 min.Water was added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried and concentrated.Toluene was added and the mixture was concentrated again. To a solutionof the obtained residue in tetrahydrofuran (40 mL) were addedphthalimide (1.85 g) and triphenylphosphine (3.30 g), 2.2M diethylazodicarboxylate/toluene solution (5.05 mL) was added dropwise underice-cooling, and the mixture was stirred at room temperature for 90 min.The reaction mixture was concentrated, and the concentrate was purifiedby silica gel column chromatography (ethyl acetate:hexane=1:10-1:2). Theobtained solid was dissolved in ethanol (60 mL)-toluene (60 mL),hydrazine monohydrate (2.05 mL) was added, and the mixture was stirredat 80° C. for 4 hr. The mixture was allowed to cool to room temperature,the solid was filtered off, and the filtrate was concentrated. Toluenewas added to the residue, and the precipitated solid was filtered off.The filtrate was concentrated to give the object compound (1.54 g)described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 4.82 (br s, 1H), 3.52-3.45 (m, 2H), 3.31 (s, 3H), 2.81(dd, 2H, J=13.0, 6.0 Hz), 2.76 (dd, 2H, J=13.0, 7.1 Hz), 1.51 (br s,2H), 1.15 (d, 3H, J=6.2 Hz).

Step 340-3

To a solution of the compound (187 mg) obtained in step 340-2 inchloroform (3 mL) were added acetone (76 μL), acetic acid (59 μL) andsodium triacetoxyborohydride (218 mg) under ice-cooling, and the mixturewas stirred at room temperature for 5 hr. The reaction mixture wasdiluted with chloroform, saturated aqueous sodium hydrogen carbonatesolution was added and the mixture was stirred. The chloroform layer wasdried and concentrated to give the object compound (190 mg) described inthe above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 4.84 (br s, 1H), 3.59-3.50 (m, 2H), 3.32 (s, 3H),2.83-2.66 (m, 3H), 1.51 (br s, 1H), 1.14 (d, 3H, J=6.4 Hz), 1.04 (d, 3H,J=6.4 Hz), 1.04 (d, 3H, J=6.4 Hz).

Step 340-4

The compound (190 mg) obtained in step 340-3 was dissolved intrifluoroacetic acid (2.0 mL), and the mixture was stood at roomtemperature for 20 min. Trifluoroacetic acid solution was concentrated,tetrahydrofuran (1.58 mL) and diisopropylethylamine (636 μL) were addedto give a solution. To a solution of the compound (75 mg) obtained instep 2-5 in tetrahydrofuran (500 μL) was added the above-mentionedsolution (634 μL), and the mixture was stirred at room temperature for15 min. Toluene (6 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (250 μL)were added and the mixture was stirred at 100° C. for 20 min. Aceticacid (750 μL) was added and the mixture was stirred at 100° C. for 1 hr.The reaction mixture was allowed to cool to room temperature, 5% aqueouspotassium hydrogen sulfate solution was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, dried, and concentrated. The concentrate was purified by silicagel thin layer chromatography (ethyl acetate:methanol=15:1) to give theobject compound (73 mg) described in the above-mentioned scheme.

¹H-NMR (CDCl₃) δ: 8.65 (s, 1H), 7.65-7.62 (m, 2H), 7.35-7.25 (m, 5H),7.04-6.98 (m, 2H), 5.51 (d, 1H, J=9.9 Hz), 5.24 (d, 1H, J=9.9 Hz), 4.94(sep, 1H, J=6.8 Hz), 4.43 (s, 2H), 3.93-3.89 (m, 1H), 3.67 (dd, 1H,J=14.2, 3.9 Hz), 3.47 (dq, 1H, J=8.8, 6.0 Hz), 3.42 (dd, 1H, J=14.2, 1.5Hz), 3.15 (s, 3H), 1.29 (d, 3H, J=6.0 Hz), 1.19 (d, 3H, J=6.8 Hz), 1.14(d, 3H, J=6.8 Hz).

Step 340-5

The compound (72 mg) obtained in step 340-4 was dissolved intrifluoroacetic acid (1.0 mL), and the mixture was stood at roomtemperature for 4 hr. Trifluoroacetic acid solution was concentrated,toluene was added and the mixture was concentrated. Ethyl acetate, 4Nhydrochloric acid/ethyl acetate solution, and hexane were added to allowcrystallization to give the object compound (65 mg) described in theabove-mentioned scheme.

¹H-NMR (DMSO-D₆) δ: 12.82 (br s, 1H), 8.72 (s, 1H), 7.44-7.41 (m, 2H),7.21-7.17 (m, 2H), 4.77 (sep, 1H, J=6.6 Hz), 4.65 (ddd, 1H, J=8.2, 4.1,0.9 Hz), 4.47 (s, 2H), 3.88 (dd, 1H, J=14.0, 4.1 Hz), 3.76 (dd, 1H,J=14.0, 0.9 Hz), 3.52 (dq, 1H, J=8.2, 6.2 Hz), 3.03 (s, 3H), 1.21 (d,3H, J=6.2 Hz), 1.20 (d, 3H, J=6.6 Hz), 1.17 (d, 3H, J=6.6 Hz).

The compounds of Examples 18 to 465 shown in the following Tables wereproduced in the same manner as in the above-mentioned Examples 1 to 17and 340, or by using other conventional methods where necessary. Thestructural formulas and property data of the compounds of Examples 18 to465 are shown in the following Tables.

TABLE 1-1 structural No. formula salt ¹H-NMR 18

— ¹H-NMR (DMSO-d₆) δ: 12.82 (s, 1H), 8.80 (s, 1H), 7.54 (td, 1H, J =8.8, 6.7 Hz), 7.29 (ddd, 1H, J = 10.2, 9.3, 2.6 Hz), 7.12 (tdd, 1H, J =8.8, 2.6 0.9 Hz), 5.01-4.93 (br m, 1H), 4.77 (sep, 1H, J = 6.7 Hz), 4.49(s, 2H), 3.84 (dd, 1H, J = 13.9, 3.9 Hz), 3.75 (dd, 1H, J = 13.9, 1.4Hz), 3.62 (dd, 1H, J = 10.2, 5.8 Hz), 3.57 (dd, 1H, J = 10.2, 7.7 Hz),3.25 (s, 3H), 1.16 (d, 3H, J = 6.7 Hz), 1.16 (d, 3H, J = 6.7 Hz). 19

— ¹H-NMR (DMSO-d₆) δ: 12.69 (br s, 1H), 8.58 (s, 1H), 7.64 (s, 1H), 7.45(td, 1H, J = 8.8, 6.8 Hz), 7.24 (ddd, 1H, J = 10.6, 9.7, 2.9 Hz), 7.07(tdd, 1H, J = 8.8, 2.9, 1.0 Hz), 4.75 (sep, 1H, J = 6.6 Hz), 4.69-4.59(br m, 1H), 4.21 (s, 2H), 3.81 (dd, 1H, J = 13.5, 3.7 Hz), 3.72 (dd, 1H,J = 13.5,1.5 Hz), 3.67 (dd, 1H, J = 11.7, 5.3 Hz), 3.53 (dd, 1H, J =11.7, 8.6 Hz), 1.16 (d, 3H, J = 6.6 Hz), 1.15 (d, 3H, J = 6.6 Hz). 20

— ¹H-NMR (DMSO-d₆) δ: 13.11 (br s, 1H), 8.60 (s, 1H), 7.66 (s, 1H), 7.44(td, 1H, J = 8.7, 6.7 Hz), 7.24 (ddd, 1H, J = 10.4, 9.3, 2.8 Hz), 7.07(tdd, 1H, J = 8.7, 2.8, 0.9 Hz), 4.79 (sep, 1H, J = 6.7 Hz), 4.21 (s,2H), 3.89 (d, 1H, J = 14.1 Hz), 3.79 (d, 1H, J = 14.1 Hz), 3.72 (d, 1H,J = 13.7 Hz), 3.63 (d, 1H, J = 13.7 Hz), 1.58 (s, 3H), 1.17 (d, 3H, J =6.7 Hz), 1.17 (d, 3H, J = 6.7 Hz).

TABLE 1-2 structural No. formula salt ¹H-NMR 21

HCl ¹H-NMR (DMSO-d₆) δ: 12.67 (s, 1H), 8.71 (s, 1H), 7.65 (s, 1H),7.49-7.41 (m, 1H), 7.33-7.20 (m, 1H), 7.11-7.02 (m, 1H), 5.11-5.02 (m,1H), 4.84-4.73 (m, 1H), 4.21 (s, 2H), 3.87-3.73 (m, 2H), 2.89-2.82 (m,2H), 2.86 (s, 3H), 2.79 (s, 3H), 1.13 (d, 3H, J = 7.0 Hz), 1.13 (d, 3H,J = 6.7 Hz). 22

— ¹H-NMR (DMSO-d₆) δ: 12.37 (s, 1H), 8.66 (s, 1H), 8.25 (q, 1H, J = 4.4Hz), 7.64 (s, 1H), 7.45 (td, 1H, J = 8.6, 6.5 Hz), 7.25 (ddd, 1H, J =10.4, 9.5, 2.8 Hz), 7.07 (tdd, 1H, J = 8.6, 2.8, 0.9 Hz), 5.52-5.46 (brm, 1H), 4.69 (sep, 1H, J = 6.7 Hz), 4.22 (s, 2H), 4.02 (dd, 1H, J =13.9, 2.1 Hz), 3.94 (dd, 1H, J = 13.9, 3.5 Hz), 2.61 (d, 3H, J = 4.4Hz), 1.12 (d, 3H, J = 6.7 Hz), 1.03 (d, 3H, J = 6.7 Hz). 23

— ¹H-NMR (DMSO-d₆) δ: 12.42 (br s, 1H), 8.75 (s. 1H), 7.65 (s, 1H), 7.46(td, 1H, J = 8.8, 7.1 Hz), 7.24 (ddd, 1H, J = 10.6, 9.7, 2.4 Hz), 7.07(tdd, 1H, J = 8.8, 2.4, 0.9 Hz), 5.71-5.66 (br m, 1H), 4.73 (sep, 1H, J= 6.7 Hz), 4.22 (s, 2H), 4.03 (dd, 1H, J = 13.5, 2.6 Hz), 3.95 (dd, 1H,J = 13.5, 4.0 Hz), 1.16 (d, 3H, J = 6.7 Hz), 1.11 (d, 3H, J = 6.7 Hz).

TABLE 1-3 structural No. formula salt ¹H-NMR 24

— ¹H-NMR (DMSO-d₆) δ: 12.90 (br s, 1H), 8.59 (s, 1H), 7.66 (s, 1H), 7.44(td, 1H, J = 9.0, 7.3 Hz), 7.24 (ddd, 1H, J = 10.8, 9.3, 2.4 Hz), 7.07(tdd, 1H, J = 9.0, 2.4, 1.0 Hz), 4.72 (sep, 1H, J = 6.7 Hz), 4.22 (s,2H), 4.05 (d, 2H, J = 13.2 Hz), 3.74 (d, 1H, J = 13.2 Hz), 1.92 (s, 3H),1.16 (d, 3H, J = 6.7 Hz), 1.14 (d, 3H, J = 6.7 Hz). 25

— ¹H-NMR (DMSO-d₆) δ: 12.39 (s, 1H), 8.66 (s, 1H), 8.36 (t, 1H, J = 5.4Hz), 7.64 (s, 1H), 7.45 (td, 1H, J = 8.7, 6.6 Hz), 7.25 (ddd, 1H, J =10.4, 9.3, 2.6 Hz), 7.07 (tdd, 1H, J = 8.7, 2.6, 0.9 Hz), 5.50-5.43 (brm, 1H), 4.70 (sep, 1H, J = 6.7 Hz), 4.22 (s, 2H), 4.03 (dd, 1H, J =13.9, 1.6 Hz), 3.95 (dd, 1H, J = 13.9, 3.7 Hz), 3.09 (qd, 2H, J = 7.4,5.4 Hz), 1.13 (d, 3H, J = 6.7 Hz), 1.05 (d, 3H, J = 6.7 Hz), 1.02 (t,3H, J = 7.4 Hz). 26

— ¹H-NMR (DMSO-d₆) δ: 12.32 (br s, 1H), 8.71 (s, 1H), 7.63 (s, 1H), 7.46(td, 1H, J = 8.7, 6.6 Hz), 7.25 (ddd, 1H, J = 10.4, 9.5, 2.6 Hz), 7.07(tdd, 1H, J = 8.7, 2.6, 1.2 Hz), 6.05-6.00 (br m, 1H), 4.71 (sep, 1H, J= 6.7 Hz), 4.21 (s, 2H), 3.98 (dd, 1H, J = 14.4, 3.9 Hz), 3.80 (dd, 1H,J = 14.4, 1.4 Hz), 3.17 (s, 3H), 2.82 (s, 3H), 1.14 (d, 3H, J = 6.7 Hz),0.98 (d, 3H, J = 6.7 Hz).

TABLE 1-4 structural No. formula salt ¹H-NMR 27

— ¹H-NMR (DMSO-d₆) δ: 12.80 (s. 1H), 8.50 (s, 1H), 8.13 (t, 1H, J = 5.4Hz), 7.66 (s, 1H), 7.44 (td, 1H, J = 8.7, 6.7 Hz), 7.24 (ddd, 1H, J =10.4, 9.3, 2.7 Hz), 7.07 (tdd, 1H, J = 8.7, 2.7, 0.9 Hz), 4.71 (sep, 1H,J = 6.7 Hz), 4.22 (s, 2H), 4.08 (d, 1H, J = 13.8 Hz), 3.78 (d, 1H, J =13.8 Hz), 3.17-2.98 (m, 2H), 1.92 (s, 3H), 1.15 (d, 3H, J = 6.7 Hz),1.11 (d, 3H, J = 6.7 Hz), 1.00 (t, 3H, J = 7.2 Hz). 28

— ¹H-NMR (DMSO-d₆) δ: 12.85 (s, 1H), 8.42 (s, 1H), 7.66 (s, 1H), 7.45(td, 1H, J = 8.7, 6.7 Hz), 7.24 (ddd, 1H, J = 10.4, 9.7, 2.8 Hz), 7.07(tdd, 1H, J = 8.7, 2.8, 0.9 Hz), 4.73 (sep, 1H, J = 6.7 Hz), 4.22 (s,2H), 4.12 (d, 1H, J = 14.1 Hz), 3.79 (d, 1H, J = 14.1 Hz), 2.93 (br s,6H), 1.97 (s, 3H), 1.17 (d, 3H, J = 6.7 Hz), 1.11 (d, 3H, J = 6.7 Hz).29

— ¹H-NMR (DMSO-d₆) δ: 12.78 (s, 1H), 8.51 (s, 1H), 8.05 (q, 1H, J = 4.2Hz), 7.66 (s, 1H), 7.44 (td, 1H, J = 8.7, 6.6 Hz), 7.24 (ddd, 1H, J =10.4, 9.5, 2.6 Hz), 7.07 (tdd, 1H, J = 8.7, 2.6, 0.9 Hz), 4.70 (sep, 1H,J = 6.7 Hz), 4.22 (s, 2H), 4.05 (d, 1H, J = 13.7 Hz), 3.78 (d, 1H, J =13.7 Hz), 2.59 (d, 3H, J = 4.2 Hz), 1.92 (s, 3H), 1.14 (d, 3H, J = 6.7Hz), 1.08 (d, 3H, J = 6.7 Hz).

TABLE 1-5 structural No. formula salt ¹H-NMR 30

HCl ¹H-NMR (DMSO-d₆) δ: 13.17 (br s, 1H), 8.87 (s, 1H), 7.54 (td, 1H, J= 8.5, 6.9 Hz), 7.29 (ddd, 1H, J = 10.5, 9.3, 2.4 Hz), 7.11 (tdd, 1H, J= 8.5, 2.4, 1.2 Hz), 4.49 (s, 2H), 3.90 (s, 2H), 3.88-3.81 (m, 2H),3.74-3.66 (m, 2H), 2.98 (ddt, 1H, J = 7.3, 6.9, 4.0 Hz), 2.28-2.19 (m,2H), 1.98-1.91 (m, 2H), 0.93-0.80 (m, 4H). 31

HCl ¹H-NMR (DMSO-d₆) δ: 12.42 (br s, 1H), 8.65 (s, 1H), 8.30 (d, 1H, J =7.4 Hz), 7.64 (s, 1H), 7.45 (td, 1H, d = 8.6, 6.5 Hz), 7.25 (ddd, 1H, J= 10.4, 9.5, 2.6 Hz), 7.07 (tdd, 1H, J = 8.6, 2.6, 0.9 Hz), 5.46-5.41(br m, 1H), 4.71 (sep, 1H, J = 6.7 Hz), 4.22 (s, 2H), 4.03 (dd, 1H, J =14.0, 1.9 Hz), 3.95 (dd, 1H, J = 14.0, 3.6 Hz), 3.85-3.74 (m, 1H), 1.13(d, 3H, J = 6.7 Hz), 1.09 (d, 3H, J = 6.7 Hz), 1.07 (d, 3H, J = 7.0 Hz),1.05 (d, 3H, J = 7.0 Hz). 32

HCl ¹H-NMR (DMSO-d₆) δ: 12.40 (br s, 1H), 3.68 (s, 1H), 8.31 (dd, 1H, J= 6.2, 5.7 Hz), 7.64 (s, 1H), 7.45 (td, 1H, J = 8.7, 6.6 Hz), 7.24 (ddd,1H, J = 10.4, 9.3, 2.8 Hz), 7.07 (tdd, 1H, J = 8.7, 2.8, 1.2 Hz),5.51-5.46 (br m, 1H), 4.68 (sep, 1H, J = 6.7 Hz), 4.21 (s, 2H), 4.04(dd, 1H, J = 14.1, 2.1 Hz), 3.94 (dd, 1H, J = 14.1, 3.6 Hz), 2.97 (ddd,1H, J = 12.8, 6.6, 6.2 Hz), 2.78 (ddd, 1H, J = 12.8, 6.6, 5.7 Hz), 1.67(sep, 1H, J = 6.5 Hz), 1.12 (d, 3H, J = 6.7 Hz), 1.04 (d, 3H, J = 6.7Hz), 0.83 (d, 3H, J = 6.5 Hz), 0.82 (d, 3H, J = 6.5 Hz).

TABLE 1-6 structural No. formula salt ¹H-NMR 33

— ¹H-NMR (DMSO-d₆) δ: 8.69 (s, 1H), 7.65 (sm 1H), 7.50-7.40 (m, 1H),7.33-7.20 (m, 1H), 7.11-7.03 (m, 1H), 5.16-5.04 (m, 1H), 4.84-4.71 (m,1H), 4.21 (s, 2H), 3.89-3.68 (m, 2H), 2.92-2.64 (m, 2H), 1.15 (t, 6H, J= 6.3 Hz). 34

HCl ¹H-NMR (DMSO-d₆) δ: 12.64 (br s, 1H), 8.54 (s, 1H), 7.95-7.87 (m,1H), 7.64 (s, 1H), 7.50-7.41 (m, 1H), 7.33-7.20 (m, 1H), 7.12-7.03 (m,1H), 5.08-4.99 (m, 1H), 4.84-4.74 (m, 1H), 4.21 (s, 2H), 3.88-3.65 (m,2H), 2.70-2.54 (m, 2H), 2.45 (d, 3H, J = 4.4 Hz), 1.17 (d, 3H, J = 6.5Hz), 1.14 (d, 3H, J = 7.2 Hz). 35

HCl ¹H-NMR (DMSO-d₆) δ: 8.58 (s, 1H), 7.65 (s, 1H), 7.49-7.38 (m, 2H),7.28-7.19 (m, 1H), 7.11-7.03 (m, 1H), 7.00 (br s, 1H), 5.07-4.97 (m,1H), 4.85-4.73 (m, 1H), 4.21 (s, 2H), 3.91-3.65 (m, 2H), 2.71-2.51 (m,2H), 1.18 (d, 3H, J = 7.0 Hz), 1.15 (d, 3H, J = 7.2 Hz). 36

HCl ¹H-NMR (DMSO-d₆) δ: 12.68 (br s, 1H), 8.46 (s, 1H), 7.85 (d, 1H, J =7.7 Hz), 7.63 (s, 1H), 7.48-7.39 (m, 1H), 7.29-7.19 (m, 1H), 7.12-7.03(m, 1H), 5.05-4.94 (m, 1H), 4.86-4.74 (m, 1H), 4.20 (s, 2H), 3.88-3.60(m, 3H), 2.70-2.46 (m, 2H), 1.18 (d, 3H, J = 7.0 Hz), 1.15 (d, 3H, J =7.2 Hz), 0.92 (d, 3H, J = 6.7 Hz), 0.69 (d, 3H, J = 6.7 Hz).

TABLE 1-7 structural No. formula salt ¹H-NMR 37

HCl ¹H-NMR (DMSO-d₆) δ: 8.80 (s, 1H), 7.57-7.49 (m, 1H), 7.32-7.25 (m,1H), 7.15-7.08 (m, 1H), 4.67 (dd, 1H, J = 13.2, 1.4 Hz), 4.51 (sep, 1H,J = 6.7 Hz), 4.48 (s, 2H), 4.34 (dd, 1H, J = 13.2, 3.5 Hz), 4.00-3.93(m, 1H), 3.57 (dd, 1H, J = 11.5, 3.5 Hz), 3.36 (dd, 1H, J = 11.5, 8.1Hz), 1.29 (d, 3H, J = 6.7 Hz), 1.28 (d, 3H, J = 6.7 Hz). 38

— ¹H-NMR (DMSO-d₆) δ: 12.97 (br s, 1H), 8.38 (s, 1H), 7.67 (s, 1H), 7.45(td, 1H, J = 8.8, 6.6 Hz), 7.25 (ddd, 1H, J = 10.2, 9.3, 2.6 Hz), 7.07(tdd, 1H, J = 8.8, 2.6, 0.9 Hz), 4.75 (sep, 1H, J = 6.7 Hz), 4.22 (s,2H), 4.03 (d, 1H, J = 13.9 Hz), 3.80 (d, 1H, J = 13.9 Hz), 3.56-3.35 (brm, 4H), 1.90 (s, 3H), 1.59-1.50 (br m, 2H), 1.49-1.40 (br m, 4H), 1.18(d, 3H, J = 6.7 Hz), 1.14 (d, 3H, J = 6.7 Hz). 39

— ¹H-NMR (DMSO-d₆) δ: 12.79 (br s, 1H), 8.52 (s, 1H), 7.66 (s, 1H), 7.45(td, 1H, J = 8.8, 6.6 Hz), 7.24 (ddd, 1H, J = 10.4, 9.5, 2.6 Hz), 7.07(tdd, 1H, J = 8.8, 2.6, 0.9 Hz), 4.70 (sep, 1H, J = 6.7 Hz), 4.21 (s,2H), 4.11 (d, 1H, J = 13.9 Hz), 3.74 (d, 1H, J = 13.9 Hz), 3.64-3.54 (brm, 1H), 3.42-3.32 (br m, 1H), 3.32-3.22 (br m, 1H), 3.15-3.05 (br m,1H), 2.00 (s, 3H), 1.94-1.82 (br m, 1H), 1.79-1.57 (br m, 3H), 1.16 (d,3H, J = 6.7 Hz), 1.07 (d, 3H, J = 6.7 Hz).

TABLE 1-8 structural No. formula salt ¹H-NMR 40

HCl ¹H-NMR (DMSO-d₆) δ: 12.92-12.53 (m, 1H), 8.44 (s, 1H), 7.97 (t, 1H,J = 6.3 Hz), 7.64 (s, 1H), 7.49-7.40 (m, 1H), 7.29-7.19 (m, 1H),7.12-7.02 (m, 1H), 5.10-4.98 (m, 1H), 4.86-4.75 (m, 1H), 4.21 (s, 2H),3.90-3.81 (m, 1H), 3.75-3.67 (m, 1H), 2.92-2.82 (m, 1H), 2.77-2.66 (m,1H), 2.61-2.48 (m, 2H), 1.44-1.30 (m, 1H), 1.18 (d, 3H, J = 7.2 Hz),1.15 (d, 3H, J = 7.2 Hz), 0.54 (d, 3H, J = 6.7 Hz), 0.50 (d, 3H, J = 7.2Hz). 41

HCl ¹H-NMR (DMSO-d₆) δ: 12.88-12.50 (m, 1H), 8.68 (s, 1H), 7.65 (s, 1H),7.49-7.40 (m, 1H), 7.28-7.20 (m, 1H), 7.11-7.03 (m, 1H), 5.11-5.03 (m,1H), 4.84-4.73 (m, 1H), 4.21 (s, 2H), 3.88-3.73 (m, 2H), 3.54-3.19 (m,4H), 2.87 (d, 2H, J = 7.0 Hz), 1.59-1.43 (m, 2H), 1.42-1.29 (m, 4H),1.13 (d, 3H, J = 6.7 Hz), 1.13 (d, 3H, J = 6.5 Hz). 42

HCl ¹H-NMR (DMSO-d₆) δ: 12.45 (br s, 1H), 8.84 (s, 1H), 7.58-7.50 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.07 (m, 1H), 4.66 (dd, 1H, J = 13.4, 1.6Hz), 4.49 (s, 2H), 4.47 (sep, 1H, J = 6.8 Hz), 4.35 (dd, 1H, J = 13.4,3.7 Hz), 4.23-4.17 (m, 1H), 3.49 (dd, 1H, J = 10.2, 4.2 Hz), 3.39 (dd,1H, J = 10.2, 7.4 Hz), 3.21 (s, 3H), 1.30 (d, 3H, J = 6.8 Hz), 1.28 (d,3H, J = 6.8 Hz).

TABLE 1-9 structural No. formula salt ¹H-NMR 43

HCl ¹H-NMR (DMSO-d₆) δ: 12.54 (br s, 1H), 8.83 (s, 1H), 7.57-7.49 (m,1H), 7.32-7.25 (m, 1H), 7.14-7.07 (m, 1H), 4.65 (dd, 1H, J = 13.4, 1.4Hz), 4.48 (s, 2H), 4.47 (dd, 1H, J = 13.4, 4.3 Hz), 4.10-4.04 (m, 1H),3.80 (dd, 1H, J = 13.3, 8.0 Hz), 3.53 (dd, 1H, J = 10.4, 5.1 Hz), 3.49(dd, 1H, J = 10.4, 6.3 Hz), 3.20 (s, 3H), 2.94 (dd, 1H, J = 13.3, 7.1Hz), 2.08 (ddsep, 1H, J = 8.0, 7.1, 6.7 Hz), 0.95 (d, 3H, J = 6.7 Hz),0.89 (d, 3H, J = 6.7 Hz). 44

HCl ¹H-NMR (DMSO-d₆) δ: 12.84 (br s, 1H), 8.81 (s, 1H), 7.59-7.49 (m,1H), 7.33-7.23 (m, 1H), 7.16-7.07 (m, 1H), 4.99-4.90 (m, 1H), 4.77 (sep,1H, J = 6.7 Hz), 4.48 (s, 2H), 3.93-3.60 (m, 4H), 3.58-3.44 (m, 2H),3.33 (t, 2H, J = 4.6 Hz), 3.11 (s, 3H), 1.17 (d, 3H, J = 6.7 Hz), 1.16(d, 3H, J = 6.7 Hz). 45

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (br s, 1H), 8.80 (s, 1H), 7.59-7.50 (m,1H), 7.35-7.24 (m, 1H), 7.16-7.07 (m, 1H), 4.97-4.86 (m, 1H), 4.49 (s,2H), 4.06 (dd, 1H, J = 13.7, 4.2 Hz), 3.80-3.66 (m, 3H), 3.59-3.46 (m,3H), 3.36-3.31 (m, 2H), 3.22 (dd, 1H, J = 7.1, 12.6 Hz), 3.11 (s, 3H),2.00 (sept, 1H, J = 6.6 Hz), 0.91 (d, 6H, J = 6.6 Hz).

TABLE 1-10 structural No. formula salt ¹H-NMR 46

HCl ¹H-NMR (DMSO-d₆) δ: 12.84 (br s, 1H), 8.81 (s, 1H), 7.59-7.49 (m,1H), 7.33-7.23 (m, 1H), 7.16-7.07 (m, 1H), 4.99-4.90 (m, 1H), 4.77 (sep,1H, J = 6.7 Hz), 4.48 (s, 2H), 3.93-3.60 (m, 4H), 3.58-3.44 (m, 2H),3.33 (t, 2H, J = 4.6 Hz), 3.11 (s, 3H), 1.17 (d, 3H, J = 6.7 Hz), 1.16(d, 3H, J = 6.7 Hz). 47

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (br s, 1H), 8.80 (s, 1H), 7.59-7.50 (m,1H), 7.35-7.24 (m, 1H), 7.16-7.07 (m, 1H), 4.97-4.86 (m, 1H), 4.49 (s,2H), 4.06 (dd, 1H, J = 13.7, 4.2 Hz), 3.80-3.66 (m, 3H), 3.59-3.46 (m,3H), 3.36-3.31 (m, 2H), 3.22 (dd, 1H, J = 7.1, 12.6 Hz), 3.11 (s, 3H),2.00 (sept, 1H, J = 6.6 Hz), 0.91 (d, 6H, J = 6.6 Hz). 48

HCl ¹H-NMR (DMSO-d₆) δ: 12.55 (br s, 1H), 8.81 (s, 1H), 7.59-7.49 (m,1H), 7.35-7.24 (m, 1H), 7.16-7.07 (m, 1H), 4.65 (d, 1H, J = 13.2 Hz),4.53-4.45 (m, 1H), 4.48 (s, 2H), 4.09-4.01 (m, 1H), 3.80 (dd, 1H, J =13.4, 7.9 Hz), 3.67-3.57 (m, 2H), 3.50-3.39 (m, 2H), 3.30-3.24 (m, 2H),3.08 (s, 3H), 2.95 (dd, 1H, J = 13.4, 7.0 Hz), 2.14-2.01 (m, 1H), 0.95(d, 3H, J = 6.5 Hz), 0.90 (d, 3H, J = 6.7 Hz). 49

HCl ¹H-NMR (DMSO-d₆) δ: 12.73 (br s, 1H), 8.80 (s, 1H), 7.67 (s, 1H),7.51-7.42 (m, 1H), 7.29-7.20 (m, 1H), 7.12-7.03 (m, 1H), 5.27-5.17 (m,1H), 4.85-4.72 (m, 1H), 4.22 (s, 2H), 3.96-3.65 (m, 2H), 3.34-3.20 (m,2H), 1.20 (d, 3H, J = 7.2 Hz), 1.14 (d, 3H, J = 7.0 Hz).

TABLE 1-11 structural No. formula salt ¹H-NMR 50

HCl ¹H-NMR (DMSO-d₆) δ: 12.38 (s, 1H), 8.95 (s, 1H), 7.57-7.50 (m,1H),7.32-7.25 (m, 1H), 7.14-7.08 (m, 1H), 5.00-4.91 (m, 2H), 4.73 (sep,1H, J = 6.6 Hz), 4.52 (dd, 1H, J = 13.6, 3.9 Hz), 4.48 (s, 2H), 1.24 (d,3H, J = 6.6 Hz), 1.13 (d, 3H, J = 6.6 Hz). 51

HCl ¹H-NMR (DMSO-d₆) δ: 12.48 (s, 1H), 8.80 (s, 1H), 8.31 (q, 1H, J =4.6 Hz), 7.57-7.49 (m, 1H), 7.33-7.24 (m, 1H), 7.14-7.07 (m, 1H), 4.76(d, 1H, J = 14.2 Hz), 4.73 (sep, 1H, J = 6.8 Hz), 4.60 (d, 1H, J = 4.0Hz), 4.54 (dd, 1H, J = 14.2, 4.0 Hz), 4.48 (s, 2H), 2.60 (d, 3H, J = 4.6Hz), 1.21 (d, 3H, J = 6.8 Hz), 1.04 (d, 3H, J = 6.8 Hz). 52

HCl ¹H-NMR (DMSO-d₆) δ: 12.95 (br s, 1H), 8.39 (s, 1H), 7.68 (s, 1H),7.45 (td, 1H, J = 8.6, 6.7 Hz), 7.25 (ddd, 1H, J = 10.2, 9.3, 2.6 Hz),7.07 (tdd, 1H, J = 8.6, 2.6, 0.9 Hz), 4.75 (sep, 1H, J = 6.7 Hz), 4.22(s, 2H), 4.02 (d, 1H, J = 14.4 Hz), 3.81 (d, 1H, J = 14.4 Hz), 3.60-3.41(br m, 8H), 1.91 (s, 3H), 1.18 (d, 3H, J = 6.7 Hz), 1.16 (d, 3H, J = 6.7Hz). 53

HCl ¹H-NMR (DMSO-d₆) δ: 12.57 (s, 1H), 8.81 (s, 1H), 7.57-7.49 (m, 1H),7.32-7.25 (m, 1H), 7.14-7.07 (m, 1H), 5.17 (d, 1H, J = 3.0 Hz), 4.80 (d,1H, J = 13.7 Hz), 4.70 (sep, 1H, J = 6.7 Hz), 4.52-4.46 (m, 1H), 4.48(s, 2H), 3.20 (s, 3H), 2.81 (s, 3H), 1.24 (d, 3H, J = 6.7 Hz), 1.00 (d,3H, J = 6.7 Hz).

TABLE 1-12 structural No. formula salt ¹H-NMR 54

HCl ¹H-NMR (DMSO-d₆) δ: 12.44 (br s, 1H), 8.81 (s, 1H), 7.59-7.48 (m,1H), 7.34-7.23 (m, 1H), 7.16-7.06 (m, 1H), 4.69-4.61 (m, 1H), 4.53-4.43(m, 1H), 4.48 (s, 2H), 4.36 (dd, 1H, J = 7.2, 13.4 Hz), 4.23-4.14 (m,1H), 3.51-3.40 (m, 4H), 3.33-3.25 (m, 2H), 3.08 (s, 3H), 1.28 (d, 3H, J= 6.7 Hz), 1.29 (d, 3H, J = 6.5 Hz). 55

HCl ¹H-NMR (DMSO-d₆) δ: 12.55 (br s, 1H), 8.81 (s, 1H), 7.59-7.49 (m,1H), 7.35-7.24 (m, 1H), 7.16-7.07 (m, 1H), 4.65 (d, 1H, J = 13.2 Hz),4.53-4.45 (m, 1H), 4.48 (s, 2H), 4.09-4.01 (m, 1H), 3.80 (dd, 1H, J =13.4, 7.9 Hz), 3.67-3.57 (m, 2H), 3.50-3.39 (m, 2H), 3.30-3.24 (m, 2H),3.08 (s, 3H), 2.95 (dd, 1H, J = 13.4, 7.0 Hz), 2.14-2.01 (m, 1H), 0.95(d, 3H, J = 6.5 Hz), 0.90 (d, 3H, J = 6.7 Hz). 56

HCl ¹H-NMR (DMSO-d₆) δ: 12.70 (br s, 1H), 8.65 (s, 1H), 7.65 (s, 1H),7.49-7.42 (m, 1H), 7.28-7.21 (m, 1H), 7.10-7.04 (m, 1H), 4.93-4.87 (m,1H), 4.77 (sep, 1H, J = 6.9 Hz), 4.21 (s, 2H), 3.82 (dd, 1H, J = 13.7,4.0 Hz), 3.76-3.67 (m, 2H), 3.62 (dd, 1H, J = 10.5, 7.7 Hz), 3.56-3.45(m, 2H), 3.35- 3.32 (m, 2H), 3.12 (s, 3H), 1.16 (d, 3H, J = 6.9 Hz),1.15 (d, 3H, J = 6.9 Hz).

TABLE 1-13 structural No. formula salt ¹H-NMR 57

HCl ¹H-NMR (DMSO-d₆) δ: 12.66 (br s, 1H), 8.64 (s, 1H), 7.65 (s, 1H),7.49-7.42 (m, 1H), 7.28-7.21 (m, 1H), 7.10-7.04 (m, 1H), 4.90-4.82 (m,1H), 4.21 (s, 2H), 4.04 (dd, 1H, J = 13.7, 4.4 Hz), 3.78-3.64 (m, 3H),3.56-3.45 (m, 2H), 3.45-3.28 (m, 3H), 3.21 (dd, 1H, J = 13.3, 6.9 Hz),3.11 (s, 3H), 2.05-1.94 (m, 1H), 0.91 (d, 6H, J = 6.4 Hz). 58

HCl ¹H-NMR (DMSO-d₆) δ: 12.40 (br s, 1H), 8.63 (s, 1H), 7.64 (s, 1H),7.49-7.41 (m, 1H), 7.28-7.20 (m, 1H), 7.11-7.04 (m, 1H), 4.62-4.55 (m,1H), 4.46 (dd, 1H, J = 13.8, 4.4 Hz), 4.21 (s, 2H), 4.06-4.00 (m, 1H),3.80 (dd, 1H, J = 13.4, 7.7 Hz), 3.64-3.54 (m, 2H), 3.50-3.40 (m, 2H),3.33-3.24 (m, 2H), 3.10 (s, 3H), 2.94 (dd, 1H, J = 13.4, 7.1 Hz),2.12-2.03 (m, 1H), 0.95 (d, 3H, J = 6.7 Hz), 0.89 (d, 3H, J = 6.7 Hz).59

HCl ¹H-NMR (DMSO-d₆) δ: 12.30 (br s, 1H), 8.62 (s, 1H), 7.64 (s, 1H),7.50-7.40 (m, 1H), 7.29-7.20 (m, 1H), 7.12-7.03 (m, 1H), 4.62-4.55 (m,1H), 4.48 (sep, 1H, J = 6.7 Hz), 4.36-4.31 (m, 1H), 4.21 (s, 2H),4.19-4.14 (m, 1H), 3.58 (dd, 1H, J = 10.3, 4.1 Hz), 3.52-3.39 (m, 3H),3.33-3.27 (m, 2H), 3.10 (s, 3H), 1.29 (d, 3H, J = 6.7 Hz), 1.28 (d, 3H,J = 6.7 Hz).

TABLE 1-14 structural No. formula salt ¹H-NMR 60

HCl ¹H-NMR (DMSO-d₆) δ: 12.44 (br s, 1H), 8.81 (s, 1H), 7.59-7.48 (m,1H), 7.34-7.23 (m, 1H), 7.16-7.06 (m, 1H), 4.69-4.61 (m, 1H), 4.53-4.43(m, 1H), 4.48 (s, 2H), 4.36 (dd, 1H, J = 7.2, 13.4 Hz), 4.23-4.14 (m,1H), 3.51-3.40 (m, 4H), 3.33-3.25 (m, 2H), 3.08 (s, 3H), 1.28 (d, 3H, J= 6.7 Hz), 1.29 (d, 3H, J = 6.5 Hz). 61

HCl ¹H-NMR (DMSO-d₆) δ: 8.66 (s, 1H), 7.49-7.41 (m, 1H), 7.29-7.21 (m,1H), 7.11-7.03 (m, 1H), 4.60 (dd, 1H, J = 13.4, 1.4 Hz), 4.47 (sep, 1H,J = 6.8 Hz), 4.33 (dd, 1H, J = 13.4, 3.7 Hz), 4.22 (s, 2H), 4.14-4.10(m, 1H), 3.48 (dd, 1H, J = 10.3, 4.3 Hz), 3.36 (dd, 1H, J = 10.3, 7.7Hz), 3.21 (s, 3H), 1.29 (d, 3H, J = 6.8 Hz), 1.28 (d, 3H, J = 6.8 Hz).62

HCl ¹H-NMR (DMSO-d₆) δ: 12.42 (br s, 1H), 8.65 (s, 1H), 7.65 (s, 1H),7.50-7.41 (m, 1H), 7.30-7.21 (m, 1H), 7.11-7.03 (m, 1H), 4.59 (dd, 1H, J= 13.7, 1.2 Hz), 4.46 (dd, 1H, J = 13.7, 4.2 Hz), 4.21 (s, 2H),4.08-4.01 (m, 1H), 3.80 (dd, 1H, J = 13.2, 7.9 Hz). 3.52 (dd, 1H, J =10.4, 5.4 Hz), 3.48 (dd, 1H, J = 10.4, 6.4 Hz), 3.20 (s, 3H), 2.93 (dd,1H, J = 13.2, 7.2 Hz), 2.08 (tt, 1H, J = 6.7, 6.7 Hz), 0.95 (d, 3H, J =6.7 Hz), 0.89 (d, 3H, J = 6.7 Hz).

TABLE 1-15 No. structural formula salt ¹H-NMR 63

HCl ¹H-NMR (CDCl₃) δ: 12.78 (br s, 1H), 9.36 (s, 1H), 7.38-7.30 (m, 1H),6.92-6.84 (m, 2H), 4.58-4.51 (m, 1H), 4.48 (s, 2H), 4.05-3.98 (m, 1H),3.76-3.63 (m, 3H), 3.51 (dd, 1H, J = 13.4, 7.9 Hz), 3.39 (s, 3H), 3.29(dd, 1H, J = 13.4, 7.0 Hz), 2.09-1.99 (m, 1H), 1.00 (d, 3H, J = 6.7 Hz),0.99 (d, 3H, J = 6.7 Hz). 64

HCl ¹H-NMR (DMSO-d₆) δ: 9.03 (s, 1H), 7.59-7.51 (m, 1H), 7.33-7.25 (m,1H), 7.16-7.08 (m, 1H), 5.66 (dd, 1H, J = 3.0, 1.9 Hz), 5.07 (dd, 1H, J= 13.8, 1.9 Hz), 4.78 (sep, 1H, J = 6.8 Hz), 4.61 (dd, 1H, J = 13.8, 3.0Hz), 4.51 (s, 2H), 1.31 (d, 3H, J = 6.8 Hz), 1.24 (d, 3H, J = 6.8 Hz).65

HCl ¹H-NMR (DMSO-d₆) δ: 8.31 (s, 1H), 7.78-7.73 (m, 2H), 7.72-7.67 (m,2H), 7.38 (td, 1H, J = 8.8, 6.8 Hz), 7.36 (s, 1H), 7.25 (ddd, 1H, J =10.4, 9.0, 2.6 Hz), 7.08 (tdd, 1H, J = 8.8, 2.6, 0.9 Hz), 4.99-4.91 (brm, 1H), 4.80 (sep, 1H, J = 6.7 Hz), 4.13 (s, 2H), 4.04 (dd, 1H, J =14.3, 4.6 Hz), 3.96 (dd, 1H, J = 13.9, 2.0 Hz), 3.89 (dd, 1H, J = 13.9,4.0 Hz), 3.82 (dd, 1H, J = 14.3,9.3 Hz), 1.27 (d, 3H, J = 6.7 Hz), 1.19(d, 3H, J = 6.7 Hz).

TABLE 1-16 No. structural formula salt ¹H-NMR 66

2HCl ¹H-NMR (DMSO-d₆) δ: 12.56 (br s, 1H), 8.70 (s, 1H), 8.25-8.13 (brm, 2H), 7.66 (s, 1H), 7.45 (td, 1H, J = 8.7, 6.7 Hz), 7.25 (ddd, 1H, J =10.4, 9.5, 2.6 Hz), 7.08 (tdd, 1H, J = 8.7, 2.6, 0.9 Hz), 4.95-4.86 (brm, 1H), 4.76 (sep, 1H, J = 6.7 Hz), 4.22 (s, 2H), 3.90 (dd, 1H, J =13.8, 3.6 Hz), 3.84 (dd, 1H, J = 13.8, 1.9 Hz), 3.35-3.24 (br m, 1H),3.22-3.09 (br m, 1H), 1.19 (d, 3H, J = 6.7 Hz), 1.15 (d, 3H, J = 6.7Hz). 67

HCl ¹H-NMR (DMSO-d₆) δ: 12.68 (br s, 1H), 8.39 (s, 1H), 8.05 (t, 1H, J =6.0 Hz), 7.64 (s, 1H), 7.46 (td, 1H, J = 8.8, 7.0 Hz), 7.25 (ddd, 1H, J= 10.4, 9.5, 2.6 Hz), 7.08 (tdd, 1H, J = 8.8, 2.6, 0.9 Hz), 4.77 (sep,1H, J = 6.7 Hz), 4.67-4.59 (br m, 1H), 4.21 (s, 2H), 3.84 (dd, 1H, J =13.8, 3.8 Hz), 3.74 (dd, 1H, J = 13.8, 0.9 Hz), 3.41-3.27 (m, 2H), 1.66(s, 3H), 1.19 (d, 3H, J = 6.7 Hz), 1.16 (d, 3H, J = 6.7 Hz). 68

HCl ¹H-NMR (DMSO-d₆) δ: 12.68 (br s, 1H), 8.36 (s, 1H), 7.97 (t, 1H, J =6.0 Hz), 7.62 (s, 1H), 7.45 (td, 1H, J = 8.7, 6.7 Hz), 7.25 (ddd, 1H, J= 10.4. 9.5, 2.6 Hz), 7.08 (tdd, 1H, J = 8.7, 2.6, 0.9 Hz), 4.77 (sep,1H, J = 6.7 Hz), 4.68-4.60 (br m, 1H), 4.21 (s, 2H), 3.84 (dd, 1H, J =13.7, 3.9 Hz), 3.75 (dd, 1H, J = 13.7, 1.4 Hz), 3.40-3.29 (m, 2H),1.96-1.86 (m, 2H), 1.19 (d, 3H, J = 6.7 Hz), 1.16 (d, 3H, J = 6.7 Hz),0.78 (t, 3H, J = 7.5 Hz).

TABLE 1-17 No. structural formula salt ¹H-NMR 69

HCl ¹H-NMR (DMSO-d₆) δ: 12.66 (s, 1H), 8.33 (s, 1H), 7.93 (t, 1H, J =6.0 Hz), 7.61 (s, 1H), 7.43 (td, 1H, J = 8.7, 6.6 Hz), 7.25 (ddd, 1H, J= 10.4, 9.5, 2.6 Hz), 7.07 (tdd, 1H, J = 8.7, 2.6, 0.9 Hz), 4.78 (sep,1H, J = 6.7 Hz), 4.69-4.61 (br m, 1H), 4.20 (s, 2H), 3.84 (dd, 1H, J =13.7, 3.9 Hz), 3.74 (dd, 1H, J = 13.7, 1.4 Hz), 3.38-3.32 (m, 2H), 2.15(sep, 1H, J = 6.7 Hz), 1.19 (d, 3H, J = 6.7 Hz), 1.16 (d, 3H, J = 6.7Hz), 0.85 (d, 3H, J = 6.7 Hz), 0.73 (d, 3H, J = 6.7 Hz). 70

HCl ¹H-NMR (DMSO-d₆) δ: 12.55 (br s, 1H), 8.75 (s, 1H), 7.58-7.50 (m,1H), 7.34-7.24 (m, 1H), 7.16-7.07 (m, 1H), 4.49 (s, 2H), 4.43-4.30 (m,3H), 4.03 (q, 1H, J = 7.8 Hz), 3.92-3.48 (m, 3H), 2.36-2.26 (m, 1H),2.12-2.00 (m, 1H), 1.39 (s, 3H), 1.36 (s, 3H). 71

HCl ¹H-NMR (DMSO-d₆) δ: 12.64 (br s, 1H), 8.49 (s, 1H), 8.04 (d, 1H, J =3.9 Hz), 7.65 (s, 1H), 7.50-7.40 (m, 1H), 7.29-7.20 (m, 1H), 7.11-7.03(m, 1H), 5.07-4.96 (m, 1H), 4.84-4.72 (m, 1H), 4.21 (s, 2H), 3.87-3.59(m, 2H), 2.71-2.30 (m, 3H), 1.15 (t, 6H, J = 7.4 Hz), 0.55-0.35 (m, 2H),0.24-0.06 (m, 2H).

TABLE 1-18 No. sructural formula salt ¹H-NMR 72

HCl ¹H-NMR (DMSO-d₆) δ: 12.69 (br s, 1H), 8.70 (s, 1H), 7.65 (s, 1H),7.49-7.39 (m, 1H), 7.29-7.19 (m, 1H), 7.11-7.00 (m, 1H), 5.14-5.01 (m,1H), 4.86-4.71 (m, 1H), 4.21 (s, 2H), 3.91-3.67 (m, 2H), 3.51-3.22 (m,8H), 2.91 (d, 2H, J = 6.5 Hz), 1.14 (d, 3H, J = 6.7 Hz), 1.13 (d, 3H, J= 6.7 Hz). 73

HCl ¹H-NMR (DMSO-d₆) δ: 8.69 (s, 1.0H), 7.65 (s, 1.0H), 7.49-7.40 (m,1.0H), 7.29-7.19 (m, 1.0H), 7.11-7.02 (m, 1.0H), 5.13-5.03 (m, 1.0H),4.84-4.72 (m, 1.0H), 4.21 (s, 2.0H), 3.88-3.55 (m, 2.0H), 3.55-3.25 (m,4.0H), 3.15 (s, 1.5H), 3.12 (s, 1.5H), 3.02-2.82 (m, 2.0H), 2.88 (s,1.5H), 2.79 (s. 1.5H), 1.13 (d, 6.0H, J = 6.5 Hz). 74

HCl ¹H-NMR (DMSO-d₆) δ: 8.85 (s, 1H), 7.57-7.50 (m, 1H), 7.32-7.25 (m,1H), 7.15-7.08 (m, 1H), 4.62-4.56 (m, 1H), 4.53-4.30 (m, 3H), 4.49 (s,2H), 2.69-2.45 (m, 2H), 1.30 (d, 3H, J = 7.2 Hz), 1.28 (d, 3H, J = 7.2Hz). 75

HCl ¹H-NMR (DMSO-d₆) δ: 12.50 (s, 1H), 8.80 (s, 1H), 7.57-7.49 (m, 1H),7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.57-4.46 (m, 2H), 4.48 (s, 2H),4.45-4.34 (m, 2H), 2.84 (s, 3H), 2.83 (s, 3H), 2.81-2.54 (m, 2H), 1.28(d, 3H, J = 6.8 Hz), 1.25 (d, 3H, J = 6.8 Hz).

TABLE 1-19 No. structural formula salt ¹H-NMR 76

HCl ¹H-NMR (DMSO-d₆) δ: 12.81-12.55 (m, 1H), 8.70 (d, 1H, J = 3.7 Hz),7.65 (s, 1H), 7.50-7.40 (m, 1H), 7.29-7.19 (m, 1H), 7.11-7.03 (m, 1H),5.13-5.02 (m, 1H), 4.86-4.72 (m, 1H), 4.21 (s, 2H), 3.88-3.73 (m, 2H),3.42-3.10 (m, 3H), 2.90-2.80 (m, 1H), 2.83 (s, 1.8H), 2.76 (s, 1.2H),1.13 (d, 3H, J = 7.0 Hz), 1.12 (d, 3H, J = 6.7 Hz), 0.99 (t, 1.2H, J =7.2 Hz), 0.93 (t 1.8H, J = 7.4 Hz). 77

HCl ¹H-NMR (DMSO-d₆) δ: 12.67 (br s, 1H), 8.68 (s, 1H), 7.65 (s, 1H),7.50-7.40 (m, 1H), 7.29-7.19 (m, 1H), 7.12-7.03 (m, 1H), 5.14-5.04 (m,1H), 4.85-4.73 (m, 1H), 4.21 (s, 2H), 3.90-3.76 (m, 2H), 3.35-3.10 (m,4H), 2.84 (d, 2H, J = 6.7 Hz), 1.13 (t, 6H, J = 6.7 Hz), 0.98 (t, 3H, J= 7.4 Hz), 0.94 (t, 3H, J = 7.4 Hz). 78

HCl ¹H-NMR (DMSO-d₆) δ: 12.66 (br s, 1H), 8.57 (s, 1H), 7.65 (s, 1H),7.45 (td, 1H, J = 8.7, 6.6 Hz), 7.36 (dd, 1H, J = 6.7, 6.1 Hz), 7.24(ddd, 1H, J = 10.4, 9.5, 2.8 Hz), 7.07 (tdd, 1H, J = 8.7, 2.8, 0.9 Hz),4.75 (sep, 1H, J = 6.7 Hz), 4.71-4.63 (br m, 1H), 4.21 (s, 2H), 3.85(dd, 1H, J = 13.8, 4.1 Hz), 3.75 (dd, 1H, J = 13.8, 1.2 Hz), 3.38 (ddd.1H, J = 14.1, 6.1, 5.6 Hz), 3.16 (ddd, 1H, J = 14.1, 9.0, 6.7 Hz), 2.89(s, 3H), 1.21 (d, 3H, J = 6.7 Hz), 1.16 (d, 3H, J = 6.7 Hz).

TABLE 1-20 No. structural formula salt ¹H-NMR 79

HCl ¹H-NMR (DMSO-d₆) δ: 8.94 (s, 1H), 7.70 (s, 1H), 7.47 (td, 1H, J =8.6, 6.8 Hz), 7.25 (ddd, 1H, J = 10.1, 9.5, 2.6 Hz), 7.08 (tdd, 1H, J =8.6, 2.6, 1.1 Hz), 6.30-6.25 (br m, 1H), 4.80 (sep, 1H, J = 6.8 Hz),4.24 (dd, 1H, J = 14.1, 2.0 Hz), 4.23 (s, 2H), 4.02 (dd, 1H, J = 14.1,3.5 Hz), 1.23 (d, 3H, J = 6.8 Hz), 1.16 (d, 3H, J = 6.8 Hz). 80

HCl ¹H-NMR (DMSO-d₆) δ: 8.35 (s, 1H), 7.64 (s, 1H), 7.46 (td, 1H, J =8.8, 7.1 Hz), 7.25 (ddd, 1H, J = 10.6, 9.5, 2.6 Hz), 7.08 (tdd, 1H, J =8.8, 2.6, 1.3 Hz), 4.92-4.84 (br m, 1H), 4.78 (sep, 1H, J = 6.7 Hz),4.21 (s, 2H), 3.87 (dd, 1H, J = 14.1, 4.4 Hz), 3.83 (dd, 1H, J = 14.1,10.8 Hz), 3.71 (dd, 1H, J = 13.9, 1.1 Hz), 3.39 (dd, 1H, J = 13.9, 4.0Hz), 2.90 (s, 3H), 1.77 (s, 3H), 1.19 (d, 3H, J = 6.7 Hz), 1.16 (d, 3H,J = 6.7 Hz). 81

HCl ¹H-NMR (DMSO-d₆) δ: 12.42 (s, 1H), 8.80 (s, 1H), 7.92 (q, 1H, J =4.4 Hz), 7.57-7.50 (m, 1H), 7.33-7.26 (m, 1H), 7.15-7.08 (m, 1H),4.53-4.30 (m, 4H), 4.49 (s, 2H), 2.56 (d, 3H, J = 4.4 Hz), 2.44-2.37 (m,2H), 1.29 (d, 3H, J = 6.8 Hz), 1.27 (d, 3H, J = 6.8 Hz).

TABLE 1-21 No. structural formula salt ¹H-NMR 82

HCl ¹H-NMR (DMSO-d₆) δ: 8.88 (s, 1H), 7.58-7.50 (m, 1H), 7.32-7.25 (m,1H), 7.15-7.08 (m, 1H), 4.64 (d, 1H, J = 13.2 Hz), 4.54-4.41 (m, 3H),4.49 (s, 2H), 3.12 (dd, 1H, J = 17.5, 7.0 Hz), 3.01 (dd, 1H, J = 17.5,4.2 Hz), 1.31 (d, 3H, J = 6.8 Hz), 1.31 (d, 3H, d = 6.8 Hz). 83

HCl ¹H-NMR (DMSO-d₆) δ: 12.42 (br s, 1H), 8.82 (s, 1H), 7.44-7.37 (m,2H), 7.22-7.14 (m, 2H), 4.68-4.62 (m, 1H), 4.55-4.42 (m, 1H), 4.47 (s,2H), 4.36 (dd, 1H, J = 13.1, 3.6 Hz), 4.23-4.13 (m, 1H), 3.52-3.39 (m,4H), 3.32-3.25 (m, 2H), 3.09 (s, 3H), 1.29 (d, 3H, J = 6.7 Hz), 1.28 (d,3H, J = 6.7 Hz). 84

HCl ¹H-NMR (DMSO-d₆) δ: 12.48 (br s, 1H), 8.82 (s, 1H), 7.44-7.36 (m,2H), 7.22-7.15 (m, 2H), 4.70-4.64 (m, 1H), 4.61-4.50 (m, 1H), 4.47 (s,2H), 4.45-4.37 (m, 1H), 4.31-4.23 (m, 1H), 3.58-3.39 (m, 4H), 3.31-3.25(m, 2H), 3.09 (s, 3H), 2.37-2.12 (m, 4H), 1.75-1.62 (m, 2H). 85

HCl ¹H-NMR (DMSO-d₆) δ: 12.82 (s, 1H), 8.80 (s, 1H), 7.54 (td, 1H, J =8.8, 6.7 Hz), 7.29 (ddd, 1H, J = 10.2, 9.3, 2.6 Hz), 7.12 (tdd, 1H, J =8.8, 2.6 0.9 Hz), 5.01-4.93 (br m, 1H), 4.77 (sep, 1H, J = 6.7 Hz), 4.49(s, 2H), 3.84 (dd, 1H, J = 13.9, 3.9 Hz), 3.75 (dd, 1H, J = 13.9, 1.4Hz), 3.62 (dd, 1H, J = 10.2, 5.8 Hz), 3.57 (dd, 1H, J = 10.2, 7.7 Hz),3.25 (s, 3H), 1.16 (d, 3H, J = 6.7 Hz). 1.16 (d, 3H. J = 6.7 Hz).

TABLE 1-22 No. structural formula salt ¹H-NMR 86

HCl ¹H-NMR (DMSO-d₆) δ: 12.73 (br s, 1H), 8.82 (s, 1H), 7.58-7.50 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 5.00-4.84 (m, 2H), 4.49 (s.2H), 3.98-3.87 (m, 2H), 3.74 (dd, 1H, J = 10.4, 6.0 Hz), 3.64 (dd, 1H, J= 10.4, 7.4 Hz), 3.58-3.46 (m, 2H), 3.34 (t, 2H, J = 4.6 Hz), 3.12 (s,3H), 2.34-2.03 (m, 4H), 1.76-1.65 (m. 2H). 87

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8.80 (s, 1H), 7.59-7.49 (m,1H), 7.35-7.24 (m, 1H), 7.16-7.07 (m, 1H), 5.01-4.93 (m, 1H), 4.77 (t,1H, J = 6.7 Hz), 4.49 (s, 2H), 3.84 (dd, 1H, J = 13.7, 3.9 Hz), 3.75(dd, 1H, J = 13.7, 2.5 Hz), 3.62 (dd, 1H, J = 10.2, 5.8 Hz), 3.57 (dd,1H, J = 10.2, 7.7 Hz), 3.25 (s, 3H), 1.16 (d, 3H, J = 6.7 Hz), 1.16 (d,3H, J = 6.7 Hz). 88

HCl ¹H-NMR (DMSO-d₆) δ: 12.82 (br s, 1H), 8.80 (s, 1H), 7.45-7.39 (m,2H), 7.22-7.15 (m, 2H), 5.01-4.94 (m, 1H), 4.77 (sep, 1H, J = 6.7 Hz),4.47 (s, 2H), 3.84 (dd, 1H, J = 13.7, 3.9 Hz), 3.75 (dd, 1H, J = 13.7,1.6 Hz), 3.62 (dd, 1H, J = 10.4, 5.8 Hz), 3.57 (dd, 1H, J = 10.4, 7.7Hz), 3.25 (s, 3H), 1.16 (d, 3H, J = 6.7 Hz), 1,16 (d, 3H, J = 6.7 Hz).89

HCl ¹H-NMR (DMSO-d₆) δ: 12.76 (br s, 1H), 8.78 (s, 1H), 7.58-7.50 (m,1H), 7.32-7.26 (m, 1H), 7.14-7.08 (m, 1H), 4.99-4.89 (m, 1H), 4.49 (s,2H), 4.07 (dd, 1H, J = 13.7, 4.4 Hz), 3.74-3.56 (m, 4H), 3.44-3.33 (m,1H), 3.25 (s, 3H), 1.14 (t, 3H, J = 7.2 Hz).

TABLE 1-23 No. structural formula salt ¹H-NMR 90

HCl ¹H-NMR (DMSO-d₆) δ: 12.47 (s, 1H), 8.87 (s, 1H), 7.57-7.49 (m, 1H),7.32-7.24 (m, 1H), 7.15-7.07 (m, 1H), 4.66 (dd, 1H, J = 13.5, 1.7 Hz),4.53 (sep, 1H, J = 6.8 Hz), 4.49 (s, 2H), 4.35-4.28 (m, 1H), 4.14-4.07(m, 1H), 3.62-3.47 (m, 2H), 1.81-1.51 (m, 2H), 1.29 (d, 6H, J = 6.8 Hz).91

HCl ¹H-NMR (DMSO-d₆) δ: 12.76-12.55 (br m, 1H), 8.61 (s, 1H), 7.61 (s,1H), 7.25 (dd, 1H, J = 8.5, 6.9 Hz), 6.92 (dd, 1H, J = 11.3, 2.4 Hz),6.73 (td, 1H, J = 8.5, 2.4 Hz), 4.94-4.86 (br m, 1H), 4.77 (sep, 1H, J =6.9 Hz), 4.09 (s, 2H), 3.84-3.79 (m, 1H), 3.83 (s, 3H), 3.76-3.69 (m,1H), 3.60 (dd, 1H, J = 10.5, 5.6 Hz), 3.54 (dd, 1H, J = 10.5, 7.7 Hz),3.23 (s, 3H), 1.16 (d, 3H, J = 6.9 Hz), 1.15 (d, 3H, J = 6.9 Hz). 92

HCl ¹H-NMR (DMSO-d₆) δ: 12.70 (br s, 1H), 8.81 (s, 1H), 7.45-7.38 (m,2H), 7.22-7.15 (m, 2H), 5.02-4.85 (m, 2H), 4.47 (s, 2H), 3.98-3.87 (m,2H), 3.65 (dd, 1H, J = 10.3, 5.8 Hz), 3.57 (dd, 1H, J = 10.3, 7.5 Hz),3.25 (s, 3H), 2.31-2.04 (m, 4H), 1.77-1.65 (m, 2H).

TABLE 1-24 No. structural formula salt ¹H-NMR 93

HCl ¹H-NMR (DMSO-d₆) δ: 8.84 (s, 1H), 7.57-7.49 (m, 1H), 7.32-7.25 (m,1H), 7.15-7.07 (m, 1H), 4.68 (d, 1H, J = 13.2 Hz), 4.60-4.49 (m, 1H),4.48 (s, 2H), 4.41 (dd, 1H, J = 13.2, 3.7 Hz), 4.32-4.25 (m, 1H), 3.43(dd, 1H, J = 10.4, 4.6 Hz), 3.39 (dd, 1H, J = 10.4, 6.8 Hz), 3.21 (s,3H), 2.39-2.11 (m, 4H), 1.77-1.63 (m, 2H). 94

HCl ¹H-NMR (DMSO-d₆) δ: 12.79 (br s, 1H), 8.60 (s, 1H), 7.67 (s, 1H),7.45 (td, 1H, J = 8.2, 6.0 Hz), 7.24 (ddd, 1H, J = 10.4, 9.5, 2.6 Hz),7.07 (tdd, 1H, J = 8.2, 2.6, 0.9 Hz), 4.70 (sep, 1H, J = 6.7 Hz), 4.22(s, 2H), 4.19-4.14 (br m, 1H), 4.09 (d, 1H, J = 14.1 Hz), 4.00 (d, 1H, J= 14.1 Hz), 3.88-3.81 (br m, 2H), 3.74-3.69 (br m, 1H), 2.14-2.04 (br m,2H), 1.94 (s, 3H), 1.16 (d, 3H, J = 6.7 Hz), 1.13 (d, 3H, J = 6.7 Hz).95

HCl ¹H-NMR (DMSO-d₆) δ: 8.84 (s, 1H), 7.43-7.38 (m, 2H), 7.21-7.14 (m,2H), 4.66 (d, 1H, J = 13.2 Hz), 4.47 (sep, 1H, J = 6.7 Hz), 4.47 (s,2H), 4.34 (dd, 1H, J = 13.5, 3.7 Hz), 4.22-4.17 (m, 1H), 3.49 (dd, 1H, J= 10.6, 4.3 Hz), 3.39 (dd, 1H, J = 10.6, 7.5 Hz), 3.21 (s, 3H), 1.30 (d,3H, J = 6.7 Hz), 1.28 (d, 3H, J = 6.7 Hz).

TABLE 1-25 No. structural formula salt ¹H-NMR 96

HCl ¹H-NMR (DMSO-d₆) δ: 12.45 (br s, 1H), 8.84 (s, 1H), 7.58-7.50 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.07 (m, 1H), 4.66 (dd, 1H, J = 13.4, 1.6Hz), 4.49 (s, 2H), 4.47 (sep, 1H, J = 6.8 Hz), 4.35 (dd, 1H, J = 13.4,3.7 Hz), 4.23-4.17 (m, 1H), 3.49 (dd, 1H, J = 10.2, 4.2 Hz), 3.39 (dd,1H, J = 10.2, 7.4 Hz), 3.21 (s, 3H), 1.30 (d, 3H, J = 6.8 Hz), 1.28 (d,3H, J = 6.8 Hz). 97

HCl ¹H-NMR (DMSO-d₆) δ: 12.76 (br s, 1H), 8.78 (s, 1H), 7.58-7.50 (m,1H), 7.32-7.26 (m, 1H), 7.14-7.08 (m, 1H), 4.99-4.89 (m, 1H), 4.49 (s,2H), 4.07 (dd, 1H, J = 13.7, 4.4 Hz), 3.74-3.56 (m, 4H), 3.44-3.33 (m,1H), 3.25 (s, 3H), 1.14 (t, 3H, J = 7.2 Hz). 98

HCl ¹H-NMR (DMSO-d₆) δ: 12.51 (br s, 1H), 8.84 (s, 1H), 7.58-7.49 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.71-4.64 (m, 1H), 4.60-4.46(m, 3H), 4.41 (dd, 1H, J = 13.7, 3.9 Hz), 4.31-4.25 (m, 1H), 3.46-3.36(m, 2H), 3.21 (s, 3H), 2.37-2.12 (m, 4H), 1.77-1.64 (m, 2H).

TABLE 1-26 No. structural formula salt ¹H-NMR  99

HCl ¹H-NMR (DMSO-d₆) δ: 12.46 (br s, 1H), 8.84 (s, 1H), 7.57-7.50 (m,1H), 7.32-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.56 (dd, 1H, J = 13.2, 1.6Hz), 4.52-4.42 (m, 1H), 4.49 (s, 2H), 4.35 (dd, 1H, J = 13.2, 4.0 Hz),4.23-4.17 (m, 1H), 3.49 (dd, 1H, J = 10.4, 4.3 Hz), 3.39 (dd, 1H, J =10.4, 7.5 Hz), 3.21 (s, 3H), 1.30 (d, 3H, J = 6.8 Hz), 1.28 (d, 3H, J =6.8 Hz). 100

HCl ¹H-NMR (DMSO-d₆) δ: 12.56 (br s, 1H), 9.02 (s, 1H), 7.53 (td, 1H, J= 8.5, 6.4 Hz), 7.29 (ddd, 1H, J = 10.5, 9.7, 2.4 Hz), 7.12 (tdd, 1H, J= 8.5. 2.4, 1.2 Hz), 4.72 (s, 2H), 4.49 (s, 2H), 4.16-4.02 (br m, 1H),3.82-3.78 (m, 2H), 3.74-3.66 (m, 2H), 2.21-2.13 (m, 2H), 1.64-1.58 (m,2H), 1.43 (d, 6H, J = 6.4 Hz). 101

HCl ¹H-NMR (DMSO-d₆) δ: 12.66 (br s, 1H), 8.66 (s, 1H), 7.66 (s, 1H),7.51-7.40 (m, 1H), 7.29-7.20 (m, 1H), 7.11-7.03 (m, 1H), 5.45-5.34 (m,1H), 4.83-4.70 (m, 1H), 4.21 (s, 2H), 3.95-3.85 (m, 2H), 3.81-3.59 (m,2H), 3.05 (s, 3H), 1.20 (d, 3H, J = 6.7 Hz), 1.14 (d, 3H, J = 6.7 Hz).

TABLE 1-27 No. structural formula salt ¹H-NMR 102

HCl ¹H-NMR (DMSO-d₆) δ: 12.50 (br s, 1H), 8.83 (s, 1H), 7.57-7.50 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.64 (dd, 1H, J = 13.7, 1.6Hz), 4.49 (s, 2H), 4.43 (dd, 1H, J = 13.7, 4.1 Hz), 4.17-4.12 (m, 1H),3.86 (dq, 1H, J = 13.4, 7.0 Hz), 3.54 (dd, 1H, J = 10.2, 5.1 Hz), 3.50(dd, 1H, J = 10.2, 6.3 Hz), 3.27 (dq, 1H, J = 13.4, 7.0 Hz), 3.21 (s,3H), 1.18 (t, 3H, J = 7.0 Hz). 103

HCl ¹H-NMR (DMSO-d₆) δ: 8.61 (s, 1H), 7.70 (s, 1H), 7.36-7.29 (m, 2H),7.18-7.11 (m, 2H), 4.80 (sep, 1H, J = 6.7 Hz), 4.20 (s, 2H), 3.74 (d,1H, J = 13.7 Hz), 3.64 (d, 1H, J = 10.4 Hz), 3.64 (d, 1H, J = 13.7 Hz),3.58 (d, 1H, J = 10.4 Hz), 3.24 (s, 3H), 1.63 (s, 3H), 1.18 (d, 3H, J =6.7 Hz), 1.17 (d, 3H, J = 6.7 Hz). 104

HCl ¹H-NMR (DMSO-d₆) δ: 12.79 (br s, 1H), 8.53 (s, 1H), 8.14 (q, 1H, J =4.4 Hz), 7.69 (s, 1H), 7.36-7.30 (m, 2H), 7.18-7.11 (m, 2H), 4.70 (sep,1H, J = 6.7 Hz), 4.21 (s, 2H), 4.09 (d, 1H, J = 13.9 Hz), 3.77 (d, 1H, J= 13.9 Hz), 2.60 (d, 3H, J = 4.4 Hz), 1.93 (s, 3H), 1.14 (d, 3H, J = 6.7Hz), 1.09 (d, 3H, J = 6.7 Hz).

TABLE 1-28 No. structural formula salt ¹H-NMR 105

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (br s, 1H), 8.52 (s, 1H), 8.18 (t, 1H, J =5.2 Hz), 7.68 (s, 1H), 7.36-7.30 (m, 2H), 7.18-7.11 (m, 2H), 4.71 (sep,1H, J = 6.7 Hz), 4.21 (s, 2H), 4.11 (d, 1H, J = 13.9 Hz), 3.78 (d, 1H, J= 13.9 Hz), 3.18-2.98 (m, 2H), 1.92 (s, 3H), 1.15 (d, 3H, J = 6.7 Hz),1.11 (d, 3H, J = 6.7 Hz), 1.00 (t, 3H, J = 7.2 Hz). 106

HCl ¹H-NMR (DMSO-d₆) δ: 12.84 (br s, 1H), 8.50 (s, 1H), 8.07 (d, 1H, J =7.4 Hz), 7.68 (s, 1H), 7.36-7.30 (m, 2H), 7.18-7.11 (m, 2H), 4.72 (sep,1H, J = 6.7 Hz), 4.21 (s, 2H), 4.16 (d, 1H, J = 14.1 Hz), 3.81 (sep, 1H,J = 6.7 Hz), 3.79 (d, 1H, J = 14.1 Hz), 1.93 (s, 3H), 1.16 (d, 3H, J =6.7 Hz), 1.15 (d, 3H, J = 6.7 Hz), 1.07 (d, 3H, J = 6.7 Hz), 1.06 (d,3H, J = 6.7 Hz). 107

HCl ¹H-NMR (DMSO-d₆) δ: 12.85 (s, 1H), 8.43 (s, 1H), 7.69 (s, 1H),7.37-7.29 (m, 2H), 7.19-7.11 (m, 2H), 4.73 (sep, 1H, J = 6.7 Hz), 4.21(s, 2H), 4.12 (d, 1H, J = 14.1 Hz), 3.79 (d, 1H, J = 14.1 Hz), 2.93 (s,6H), 1.98 (s, 3H), 1.17 (d, 3H, J = 6.7 Hz), 1.11 (d, 3H, J = 6.7 Hz).

TABLE 1-29 No. structural formula salt ¹H-NMR 108

HCl ¹H-NMR (DMSO-d₆) δ: 12.96 (br s, 1H), 8.39 (s, 1H), 7.69 (s, 1H),7.37-7.30 (m, 2H), 7.19-7.11 (m, 2H), 4.75 (sep, 1H, J = 6.7 Hz), 4.21(s, 2H), 4.03 (d, 1H, J = 14.4 Hz), 3.80 (d, 1H, J = 14.4 Hz), 3.56-3.37(br m, 4H), 1.90 (s, 3H), 1.59-1.50 (br m, 2H), 1.50-1.41 (br m, 4H),1.18 (d, 3H, J = 6.7 Hz), 1.14 (d, 3H, J = 6.7 Hz). 109

HCl ¹H-NMR (DMSO-d₆) δ: 12.79 (br s, 1H), 8.54 (s, 1H), 7.69 (s, 1H),7.37-7.30 (m, 2H), 7.19-7.11 (m, 2H), 4.70 (sep, 1H, J = 6.7 Hz), 4.21(s, 2H), 4.12 (d, 1H, J = 14.1 Hz), 3.75 (d, 1H, J = 14.1 Hz), 3.65-3.53(br m, 1H), 3.43-3.33 (br m, 1H), 3.33-3.23 (br m, 1H), 3.16-3.05 (br m,1H), 2.01 (s, 3H), 1.94-1.84 (br m, 1H), 1.81-1.56 (br m, 3H), 1.16 (d,3H, J = 6.7 Hz), 1.08 (d, 3H, J = 6.7 Hz). 110

HCl ¹H-NMR (DMSO-d₆) δ: 13.12 (s, 1H), 8.63 (s, 1H), 7.69 (s, 1H),7.36-7.30 (m, 2H), 7.18-7.11 (m, 2H), 4.79 (sep, 1H, J = 6.7 Hz), 4.20(s, 2H), 3.74 (d, 1H, J = 10.2 Hz), 3.73 (d, 1H, J = 13.9 Hz), 3.66 (d,1H, J = 10.2 Hz), 3.65 (d, 1H, J = 13.9 Hz), 3.54-3.42 (m, 2H),3.38-3.30 (m, 2H), 3.11 (s, 3H), 1.63 (s, 3H), 1.18 (d, 3H, J = 6.7 Hz),1.17 (d, 3H, J = 6.7 Hz).

TABLE 1-30 No. structural formula salt ¹H-NMR 111

HCl ¹H-NMR (DMSO-d₆) δ: 13.14 (s, 1H), 8.63 (s, 1H), 7.69 (s, 1H),7.36-7.30 (m, 2H), 7.18-7.11 (m, 2H), 4.79 (sep, 1H, J = 6.7 Hz), 4.21(s, 2H), 3.72 (d, 1H, J = 13.7 Hz), 3.64 (d, 1H, J = 13.7 Hz), 3.61 (s,2H), 1.59 (s, 3H), 1.17 (d, 3H, J = 6.7 Hz), 1.17 (d, 3H, J = 6.7 Hz).112

HCl ¹H-NMR (DMSO-d₆) δ: 12.87 (br s, 1H), 8.61 (s, 1H), 7.70 (s, 1H),7.37-7.30 (m, 2H), 7.18-7.11 (m, 2H), 4.73 (sep, 1H, J = 6.7 Hz), 4.21(s, 2H), 4.06 (d, 1H, J = 13.7 Hz), 3.80 (d, 1H, J = 13.7 Hz), 1.98 (s,3H), 1.16 (d, 3H, J = 6.7 Hz), 1.14 (d, 3H, J = 6.7 Hz). 113

HCl ¹H-NMR (DMSO-d₆) δ: 12.64-12.34 (m, 1H), 8.83 (s, 1H), 7.44-7.37 (m,2H), 7.22-7.14 (m, 2H), 4.64 (dd, 1H, J = 13.4, 1.5 Hz), 4.47 (s, 2H),4.42 (dd, 1H, J = 13.4, 4.4 Hz), 4.17-4.11 (m, 1H), 3.86 (dq, 1H, J =14.0, 7.0 Hz), 3.54 (dd, 1H, J = 10.4, 4.9 Hz), 3.50 (dd, 1H, J = 10.4,6.3 Hz), 3.27 (dq, 1H, J = 14.0, 7.0 Hz), 3.22 (s, 3H), 1.20 (t, 3H, J =7.0 Hz).

TABLE 1-31 No. structural formula salt ¹H-NMR 114

HCl ¹H-NMR (DMSO-d₆) δ: 12.50 (br s, 1H), 8.83 (s, 1H), 7.57-7.50 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.64 (dd, 1H, J = 13.7, 1.6Hz), 4.49 (s, 2H), 4.43 (dd, 1H, J = 13.7, 4.1 Hz), 4.17-4.12 (m, 1H),3.86 (dq, 1H, J = 13.4, 7.0 Hz), 3.54 (dd, 1H, J = 10.2, 5.1 Hz), 3.50(dd, 1H, J = 10.2, 6.3 Hz), 3.27 (dq, 1H, J = 13.4, 7.0 Hz), 3.21 (s,3H), 1.18 (t, 3H, J = 7.0 Hz). 115

HCl ¹H-NMR (DMSO-d₆) δ: 12.72 (br s, 1H), 8.79 (s, 1H), 7.44-7.37 (m,2H), 7.22-7.15 (m, 2H), 4.61 (dd, 1H, J = 13.6, 1.6 Hz), 4.47 (s, 2H),4.35 (dd, 1H, J = 13.6, 4.2 Hz), 3.86-3.80 (m, 1H), 3.62 (dd, 1H, J =11.5, 3.8 Hz), 3.52 (dd, 1H, J = 11.5, 7.1 Hz), 2.95-2.88 (m, 1H),1.03-0.94 (m, 1H), 0.90-0.83 (m, 1H), 0.83-0.72 (m, 2H). 116

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (s, 1H), 8.79 (s, 1H), 7.46-7.38 (m, 2H),7.24-7.15 (m, 2H), 5.02-4.90 (m, 1H), 4.47 (s, 2H), 4.12 (dd, 1H, J =13.7, 3.9 Hz), 3.87-3.79 (m, 1H), 3.73-3.58 (m, 2H), 3.45 (dd, 1H, J =14.0, 7.3 Hz), 3.31 (dd, 1H, J = 14.0, 6.8 Hz), 3.26 (s, 3H), 1.15- 1.03(m, 1H), 0.58-0.46 (m, 2H), 0.39-0.26 (m, 2H).

TABLE 1-32 No. structural formula salt ¹H-NMR 117

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (br s, 1H), 8.79 (s, 1H), 7.59-7.50 (m,1H), 7.33-7.26 (m, 1H), 7.15-7.08 (m, 1H), 4.99-4.92 (m, 1H), 4.49 (s,2H), 4.12 (dd, 1H, J = 13.8, 4.3 Hz), 3.87-3.80 (m, 1H), 3.69 (dd, 1H, J= 10.4, 5.6 Hz), 3.62 (dd, 1H, J = 10.4, 7.9 Hz), 3.45 (dd, 1H, J =13.8, 7.3 Hz), 3.31 (dd, 1H, J = 13.9, 7.0 Hz), 3.26 (s, 3H), 1.14-1.03(m, 1H), 0.57-0.46 (m, 2H), 0.39-0.27 (m, 2H). 118

HCl ¹H-NMR (DMSO-d₆) δ: 12.76 (s, 1H), 8.80 (s, 1H), 7.45-7.38 (m, 2H),7.23-7.15 (m, 2H), 4.96-4.89 (m, 1H), 4.47 (s, 2H), 4.11 (dd, 1H, J =13.7, 4.2 Hz), 3.84 (dd, 1H, J = 13.7, 1.2 Hz), 3.78 (dd, 1H, J = 10.5,5.6 Hz), 3.70 (dd, 1H, J = 10.5, 7.7 Hz), 3.59-3.39 (m, 3H), 3.37-3.29(m, 3H), 3.10 (s, 3H), 1.13-1.04 (m, 1H), 0.58-0.46 (m, 2H), 0.38-0.27(m, 2H). 119

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (br s, 1H), 8.80 (s, 1H), 7.58-7.50 (m,1H), 7.33-7.25 (m, 1H), 7.16-7.08 (m, 1H), 4.97-4.89 (m, 1H), 4.49 (s,2H), 4.12 (dd, 1H, J = 13.7, 4.4 Hz), 3.84 (dd, 1H, J = 13.7, 1.2 Hz),3.78 (dd, 1H, J = 10.5, 5.6 Hz), 3.70 (dd, 1H, J = 10.5, 7.7 Hz),3.59-3.40 (m, 3H), 3.37-3.29 (m, 3H), 3.10 (s, 3H), 1.14-1.04 (m, 1H),0.58-0.47 (m, 2H), 0.38-0.27 (m, 2H).

TABLE 1-33 No. structural formula salt ¹H-NMR 120

HCl ¹H-NMR (DMSO-d₆) δ: 12.42 (br s, 1H), 8.82 (s, 1H), 7.44-7.37 (m,2H), 7.22-7.14 (m, 2H), 4.65 (d, 1H, J = 12.5 Hz), 4.55-4.42 (m, 1H),4.47 (s, 2H), 4.36 (dd, 1H, J = 13.1, 3.6 Hz), 4.23-4.13 (m, 1H),3.52-3.39 (m, 4H), 3.32-3.25 (m, 2H), 3.09 (s, 3H), 1.29 (d, 3H, J = 6.7Hz), 1.28 (d, 3H, J = 6.7 Hz). 121

HCl ¹H-NMR (DMSO-d₆) δ: 13.10 (br s, 1H), 8.58 (s, 1H), 7.66 (s, 1H),7.44 (td, 1H, J = 8.7, 6.7 Hz), 7.23 (ddd, 1H, J = 10.4, 9.5, 2.6 Hz),7.06 (tdd, 1H, J = 8.7, 2.6, 0.9 Hz), 4.78 (sep, 1H, J = 6.7 Hz), 4.20(s, 2H), 3.73 (d, 1H, J = 13.9 Hz), 3.63 (d, 1H, J = 13.9 Hz), 3.63 (d,1H, J = 10.2 Hz), 3.56 (d, 1H, J = 10.2 Hz), 3.22 (s, 3H), 1.61 (s, 3H),1.16 (d, 3H, J = 6.7 Hz), 1.16 (d, 3H, J = 6.7 Hz). 122

HCl ¹H-NMR (DMSO-d₆) δ: 13.12 (br s, 1H), 8.62 (s, 1H), 7.67 (s, 1H),7.45 (td, 1H, J = 8.8, 7.0 Hz), 7.25 (ddd, 1H, J = 10.4, 9.3, 2.6 Hz),7.07 (tdd, 1H, J = 8.8, 2.6, 1.0 Hz), 4.79 (sep, 1H, J = 6.7 Hz), 4.21(s, 2H), 3.78-3.70 (m, 2H), 3.66 (d, 1H, J = 10.2 Hz), 3.65 (d, 1H, J =13.9 Hz), 3.54-3.42 (m, 2H), 3.37-3.29 (m, 2H), 3.11 (s, 3H), 1.63 (s,3H), 1.18 (d, 3H, J = 6.7 Hz), 1.17 (d, 3H, J = 6.7 Hz).

TABLE 1-34 No. structural formula salt ¹H-NMR 123

HCl ¹H-NMR (DMSO-d₆) δ: 12.78 (s, 1H), 8.82 (s, 1H), 7.45-7.38 (m, 2H),7.22-7.15 (m, 2H), 4.93-4.86 (m, 1H), 4.47 (s, 2H), 4.19 (dd, 1H, J =13.7, 4.2 Hz), 3.82 (dd, 1H, J = 10.4, 5.6 Hz), 3.78-3.70 (m, 2H),3.58-3.47 (m, 2H), 3.42 (d, 1H, J = 13.4 Hz), 3.35-3.31 (m, 2H), 3.23(d, 1H, J = 13.4 Hz), 3.11 (s, 3H), 0.98 (s, 9H). 124

HCl ¹H-NMR (DMSO-d₆) δ: 12.78 (br s, 1H), 8.80 (s, 1H), 7.57-7.50 (m,1H), 7.32-7.24 (m, 1H), 7.14-7.07 (m, 1H), 4.92-4.85 (m, 1H), 4.48 (s,2H), 4.18 (dd, 1H, J = 13.7, 4.2 Hz), 3.81 (dd, 1H, J = 10.6, 5.7 Hz),3.76-3.69 (m, 2H), 3.56-3.46 (m, 2H), 3.41 (d, 1H, J = 13.4 Hz),3.34-3.30 (m, 2H), 3.22 (d, 1H, J = 13.4 Hz), 3.09 (s, 3H), 0.97 (s,9H). 125

HCl ¹H-NMR (DMSO-d₆) δ: 12.78 (br s, 1H), 8.79 (s, 1H), 7.58-7.50 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.96-4.88 (m, 1H), 4.49 (s,2H), 4.07 (dd, 1H, J = 13.6, 4.3 Hz), 3.79-3.59 (m, 4H), 3.57-3.45 (m,2H), 3.45-3.36 (m, 1H), 3.33 (t, 2H, J = 4.6 Hz), 3.10 (s, 3H), 1.15 (t,3H, J = 7.2 Hz).

TABLE 1-35 No. structural formula salt ¹H-NMR 126

HCl ¹H-NMR (DMSO-d₆) δ: 12.47 (br s, 1H), 8.83 (s, 1H), 7.56-7.49 (m,1H), 7.32-7.24 (m, 1H), 7.14-7.07 (m, 1H), 4.66 (dd, 1H, J = 13.4, 1.6Hz), 4.48 (s, 2H), 4.44 (dd, 1H, J = 13.4, 4.2 Hz), 4.25-4.20 (m, 1H),3.68 (dd, 1H, J = 14.0, 7.0 Hz), 3.57 (dd, 1H, J = 10.2, 4.6 Hz), 3.50(dd, 1H, J = 10.2, 6.5 Hz), 3.20 (dd, 1H, J = 14.0, 7.0 Hz), 3.20 (s,3H), 1.20-1.09 (m, 1H), 0.58-0.46 (m, 2H), 0.43-0.35 (m, 1H), 0.35-0.27(m, 1H). 127

HCl ¹H-NMR (DMSO-d₆) δ: 12.78 (br s, 1H), 8.79 (s, 1H), 7.58-7.50 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.96-4.88 (m, 1H), 4.49 (s,2H), 4.07 (dd, 1H, J = 13.6, 4.3 Hz), 3.79-3.59 (m, 4H), 3.57-3.45 (m,2H), 3.45-3.36 (m, 1H), 3.33 (t, 2H, J = 4.6 Hz), 3.10 (s, 3H), 1.15 (t,3H, J = 7.2 Hz). 128

HCl ¹H-NMR (DMSO-d₆) δ: 12.77 (br s, 1H), 8.80 (s, 1H), 7.44-7.39 (m,2H), 7.22-7.15 (m, 2H), 4.95-4.88 (m, 1H), 4.47 (s, 2H), 4.07 (dd, 1H, J= 13.6, 4.3 Hz), 3.78-3.60 (m, 4H), 3.57-3.46 (m, 2H), 3.43-3.37 (m,1H), 3.33 (t, 2H, J = 4.6 Hz), 3.10 (s, 3H), 1.15 (t, 3H, J = 7.2 Hz).

TABLE 1-36 No. structural formula salt ¹H-NMR 129

HCl ¹H-NMR (DMSO-d₆) δ: 12.67 (s, 1H), 8.83 (s, 1H), 7.59-7.49 (m, 1H),7.34-7.25 (m, 1H), 7.16-7.07 (m, 1H), 4.70-4.55 (m, 2H), 4.49 (s, 2H),4.03-3.97 (br m, 1H), 3.95 (d, 1H, J = 13.4 Hz), 3.66-3.59 (m, 2H),3.47-3.41 (m, 2H), 3.27- 3.22 (m, 2H), 3.07 (s, 3H), 2.85 (d, 1H, J =13.4 Hz), 0.98 (s, 9H). 130

HCl ¹H-NMR (DMSO-d₆) δ: 12.50 (s, 1H), 8.80 (s, 1H), 7.59-7.49 (m, 1H),7.34-7.25 (m, 1H), 7.15-7.07 (m, 1H), 4.68-4.59 (m, 1H), 4.48 (s, 2H),4.43 (dd, 1H, J = 13.4, 4.2 Hz), 4.17-4.09 (m, 1H), 3.86 (td, 1H, J =13.9, 7.0 Hz), 3.67- 3.56 (m, 2H), 3.52-3.41 (m, 2H), 3.34-3.22 (m, 3H),3.09 (s, 3H), 1.20 (t, 3H, J = 7.0 Hz). 131

HCl ¹H-NMR (DMSO-d₆) δ: 12.97-12.84 (br m, 1H), 8.76 (s, 1H), 7.58-7.50(m, 1H), 7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.92-4.85 (br m, 1H),4.48 (s, 2H), 3.98-3.84 (m, 2H), 3.67 (dd, 1H, J = 10.1, 5.6 Hz), 3.59(dd, 1H, J = 10.1, 7.7 Hz), 3.28 (s, 3H), 1.48 (s, 9H).

TABLE 1-37 No. structural formula salt ¹H-NMR 132

HCl ¹H-NMR (DMSO-d₆) δ: 12.79 (br s, 1H), 8.90 (s, 1H), 7.58-7.50 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.97-4.88 (m, 1H), 4.84-4.74(m, 1H), 4.49 (s, 2H), 3.81 (dd, 1H, J = 13.5, 3.7 Hz), 3.63 (dd, 1H, J= 13.5, 2.2 Hz), 1.39 (d, 3H, J = 6.6 Hz), 1.19 (d, 3H, J = 6.8 Hz),1.16 (d, 3H, J = 6.8 Hz). 133

HCl ¹H-NMR (DMSO-d₆) δ: 12.48 (s, 1H), 8.80 (s, 1H), 7.57-7.50 (m, 1H),7.32-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.67 (d, 1H, J = 13.1 Hz), 4.51(sep, 1H, J = 6.8 Hz), 4.49 (s, 2H), 4.34 (dd, 1H, J = 13.1, 3.7 Hz),4.00-3.93 (m, 1H), 3.57 (dd, 1H, J = 11.4, 3.7 Hz), 3.37 (dd, 1H, J =11.4, 8.3 Hz), 1.29 (d, 3H, J = 6.7 Hz), 1.28 (d, 3H, J = 6.7 Hz). 134

HCl ¹H-NMR (DMSO-d₆) δ: 12.88 (br s, 1H), 8.83-8.80 (m, 1H), 7.59-7.50(m, 1H), 7.33-7.24 (m, 1H), 7.16-7.08 (m, 1H), 5.01-4.90 (br m, 1H),4.60-4.50 (m, 1H), 4.49 (s, 2H) 3.87-3.63 (m, 4H), 3.57-3.46 (m, 2H),3.35-3.30 (m, 2H), 3.12-3.10 (m, 3H), 1.59-1.48 (m, 2H), 1.15 (d, 3H, J= 6.7 Hz), 0.91-0.78 (m, 3H).

TABLE 1-38 No. structural formula salt ¹H-NMR 135

HCl ¹H-NMR (DMSO-d₆) δ: 12.89 (br s, 1H), 8.81 (s, 1H), 7.59-7.50 (m,1H), 7.34-7.25 (m, 1H), 7.16-7.06 (m, 1H), 5.03-4.92 (br m, 1H),4.59-4.50 (m, 1H), 4.49 (s, 2H), 3.73-3.54 (m, 4H), 3.26-3.23 (m, 3H),1.61-1.45 (m, 2H), 1.15 (d, 3H, J = 6.7 Hz), 0.91-0.80 (m, 3H). 136

HCl ¹H-NMR (DMSO-d₆) δ: 12.96 (br s, 1H), 8.82 (s, 1H), 7.59-7.49 (m,1H), 7.35-7.24 (m, 1H), 7.17-7.06 (m, 1H), 5.04-4.91 (m, 1H), 4.49 (s,2H), 4.30-3.57 (m, 5H), 3.27-3.22 (m, 3H), 1.87-1.69 (m, 1H), 1.17 (d,3H, J = 6.8 Hz), 0.97-0.79 (m, 6H). 137

HCl ¹H-NMR (DMSO-d₆) δ: 12.42 (br s, 1H), 8.71 (s, 1H), 8.23-8.17 (m,1H), 7.58-7.50 (m, 1H), 7.33-7.26 (m, 1H), 7.15-7.08 (m, 1H), 4.58 (sep,1H, J = 6.7 Hz), 4.49 (s, 2H), 4.43 (dd, 1H, J = 13.0, 1.3 Hz), 4.31(dd, 1H, J = 13.0, 3.0 Hz), 3.97-3.91 (m, 1H), 3.45-3.36 (m, 1H),2.97-2.86 (m, 1H), 1.80 (s, 3H), 1.34 (d, 3H, J = 6.7 Hz), 1.27 (d, 3H,J = 6.7 Hz). 138

HCl ¹H-NMR (DMSO-d₆) δ: 12.49 (br s, 1H), 8.72 (s, 1H), 7.88-7.83 (m,1H), 7.57-7.50 (m, 1H), 7.32-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.57 (sep,1H, J = 6.7 Hz), 4.49 (s, 2H), 4.38-4.28 (m, 2H), 3.99-3.92 (m, 1H),3.38-3.29 (m, 1H), 3.04-2.95 (m, 1H), 1.38 (d, 3H, J = 6.7 Hz), 1.29 (d,3H, J = 6.7 Hz), 1.08 (s, 9H).

TABLE 1-39 No. structural formula salt ¹H-NMR 139

HCl ¹H-NMR (DMSO-d₆) δ: 13.18 (br s, 1H), 8.47 (s, 1H), 7.67 (s, 1H),7.46 (td, 1H, J = 8.8, 6.6 Hz), 7.25 (ddd, 1H, J = 10.4, 9.3, 2.6 Hz),7.08 (tdd, 1H, J = 8.8, 2.6, 0.9 Hz), 4.79 (sep, 1H, J = 6.7 Hz), 4.21(s, 2H), 3.79 (d, 1H, J = 13.9 Hz), 3.74 (d, 1H, J = 14.6 Hz), 3.68 (d,1H, J = 13.9 Hz), 3.57 (d, 1H, J = 14.6 Hz), 2.75 (s, 3H), 1.81 (s, 3H),1.67 (s, 3H), 1.22 (d, 3H, J = 6.7 Hz), 1.17 (d, 3H, J = 6.7 Hz). 140

HCl ¹H-NMR (DMSO-d₆) δ: 12.42 (br s, 1H), 8.71 (s, 1H), 8.22-8.17 (m,1H), 7.57-7.50 (m, 1H), 7.33-7.26 (m, 1H), 7.15-7.08 (m, 1H), 4.58 (sep,1H, J = 6.8 Hz), 4.49 (s, 2H), 4.43 (d, 1H, J = 13.0 Hz), 4.30 (dd, 1H,J = 13.0, 3.0 Hz), 3.98-3.91 (m, 1H), 2.96-2.86 (m, 1H), 2.56-2.50 (m,1H), 1.80 (s, 3H), 1.34 (d, 3H, J = 6.8 Hz), 1.27 (d, 3H, J = 6.8 Hz).141

HCl ¹H-NMR (DMSO-d₆) δ: 12.84 (s, 1H), 8.82 (s, 1H), 7.45-7.38 (m, 2H),7.23-7.15 (m, 2H), 4.99-4.91 (m, 1H), 4.77 (sep, 1H, J = 6.8 Hz), 4.47(s, 2H), 3.84 (dd, 1H, J = 13.8, 4.1 Hz), 3.75 (dd, 1H, J = 13.8, 1.7Hz), 3.66 (dd, 1H, J = 10.4, 6.0 Hz), 3.59 (dd, 1H, J = 10.4, 7.5 Hz),3.50-3.34 (m, 2H), 1.17 (d, 3H, J = 6.8 Hz), 1.16 (d, 3H, J = 6.8 Hz),1.02 (t, 3H, J = 7.1 Hz).

TABLE 1-40 No. structural formula salt ¹H-NMR 142

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8.81 (s, 1H), 7.58-7.51 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.07 (m, 1H), 4.98-4.91 (m, 1H), 4.77 (sep,1H, J = 6.8 Hz), 4.49 (s, 2H), 3.84 (dd, 1H, J = 13.7, 4.0 Hz),3.78-3.73 (m, 1H), 3.69-3.56 (m, 2H), 3.50-3.34 (m, 2H), 1.17 (d, 3H, J= 6.8 Hz), 1.16 (d, 3H, J = 6.8 Hz), 1.02 (t, 3H, J = 7.1 Hz). 143

HCl ¹H-NMR (DMSO-d₆) δ: 12.85 (br s, 1H), 8.80 (s, 1H), 7.58-7.50 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.99-4.92 (m, 1H), 4.77 (sep,1H, J = 6.7 Hz), 4.48 (s, 2H), 3.84 (dd, 1H, J = 13.8, 4.1 Hz),3.79-3.68 (m, 2H), 3.65 (dd, 1H, J = 10.4, 7.9 Hz), 3.56-3.44 (m, 2H),3.38-3.34 (m, 2H), 3.30-3.22 (m, 2H), 1.17 (d, 3H, J = 6.7 Hz), 1.16 (d,3H, J = 6.7 Hz), 0.91 (t, 3H, J = 7.0 Hz). 144

HCl ¹H-NMR (DMSO-d₆) δ: 12.82 (br s, 1H), 8.81 (s, 1H), 7.52-7.38 (m,2H), 7.26-7.21 (m, 1H), 5.00-4.94 (m, 1H), 4.77 (sep, 1H, J = 6.9 Hz),4.49 (s, 2H), 3.84 (dd, 1H, J = 13.7, 4.0 Hz), 3.75 (dd, 1H, J = 13.7,1.2 Hz), 3.66-3.54 (m, 2H), 3.25 (s, 3H), 1.16 (d, 3H, J = 6.9 Hz), 1.16(d, 3H, J = 6.9 Hz).

TABLE 1-41 No. structural formula salt ¹H-NMR 145

HCl ¹H-NMR (DMSO-d₆) δ: 12.45 (br s, 1H), 8.85 (s, 1H), 7.58-7.50 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.71-4.65 (m, 1H), 4.49 (s,2H), 4.38-4.27 (m, 2H), 4.17-4.11 (m, 1H), 3.50 (dd, 1H, J = 10.5, 4.1Hz), 3.39 (dd, 1H, J = 10.5, 7.7 Hz), 3.20 (s, 3H), 1.78-1.59 (m, 2H),1.25 (d, 3H, J = 6.8 Hz), 0.86 (t, 3H, J = 7.4 Hz). 146

HCl ¹H-NMR (DMSO-d₆) δ: 12.48 (br s, 1H), 8.83 (s, 1H), 7.57-7.50 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.65 (dd, 1H, J = 13.5, 1.1Hz), 4.49 (s, 2H), 4.38 (dd, 1H, J = 13.5, 4.1 Hz), 4.15-4.03 (m, 2H),3.50 (dd, 1H, J = 10.1, 4.2 Hz), 3.42 (dd, 1H, J = 10.1, 7.1 Hz), 3.20(s, 3H), 1.83-1.73 (m, 1H), 1.63-1.53 (m, 1H), 1.33 (d, 3H, J = 6.8 Hz),0.91 (t, 3H, J = 7.4 Hz). 147

HCl ¹H-NMR (DMSO-d₆) δ: 12.85 (br s, 1H), 8.81 (s, 1H), 7.59-7.49 (m,1H), 7.33-7.25 (m, 1H), 7.16-7.08 (m, 1H), 5.05-4.86 (br m, 1H),4.60-4.50 (m, 1H), 4.49 (s, 2H), 3.87-3.56 (m, 4H), 3.25-3.25 (m, 3H),1.54-1.50 (m, 2H), 1.15 (d, 3H, J = 6.5 Hz), 0.91-0.80 (m, 3H).

TABLE 1-42 No. structural formula salt ¹H-NMR 148

HCl ¹H-NMR (DMSO-d₆) δ: 12.87 (br s, 1H), 8.81 (s, 1H), 7.58-7.52 (m,1H), 7.32-7.27 (m, 1H), 7.16-7.07 (m, 1H), 5.05-4.90 (m, 1H), 4.49 (s,2H), 4.32-4.20 (m, 1H), 3.90-3.57 (m, 4H), 3.26-3.24 (m, 3H), 1.87-1.69(m, 1H), 1.19-1.10 (m, 3H), 0.97-0.79 (m, 6H). 149

HCl ¹H-NMR (DMSO-d₆) δ: 12.79 (br s, 1H), 8.90 (s, 1H), 7.58-7.50 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.97-4.88 (m, 1H), 4.84-4.74(m, 1H), 4.49 (s, 2H), 3.81 (dd, 1H, J = 13.5, 3.7 Hz), 3.63 (dd, 1H, J= 13.5, 2.2 Hz), 1.39 (d, 3H, J = 6.6 Hz), 1.19 (d, 3H, J = 6.8 Hz),1.16 (d, 3H, J = 6.8 Hz). 150

HCl ¹H-NMR (DMSO-d₆) δ: 12.44 (br s, 1H), 8.85 (s, 1H), 7.53-7.37 (m,2H), 7.26-7.19 (m, 1H), 4.66 (dd, 1H, J = 13.5, 1.5 Hz), 4.51-4.43 (m,1H), 4.49 (s, 2H), 4.38-4.32 (m, 1H), 4.23-4.17 (m, 1H), 3.49 (dd, 1H, J= 10.4, 4.4 Hz), 3.39 (dd, 1H, J = 10.4, 7.5 Hz), 3.22 (s, 3H), 1.30 (d,3H, J = 6.6 Hz), 1.29 (d, 3H, J = 6.8 Hz).

TABLE 1-43 No. structural formula salt ¹H-NMR 151

HCl ¹H-NMR (DMSO-d₆) δ: 12.86-12.34 (m, 1H), 8.68 (s, 1H), 7.66 (s, 1H),7.49-7.39 (m, 1H), 7.29-7.20 (m, 1H), 7.11-7.02 (m, 1H), 5.12-5.03 (m,1H), 4.84-4.70 (m, 1H), 4.21 (s, 2H), 3.82-3.55 (m, 2H), 3.15-2.96 (m,2H), 2.08 (s, 3H), 1.17-1.09 (m, 6H). 152

HCl ¹H-NMR (DMSO-d₆) δ: 12.77 (br s, 1H), 8.43 (s, 1H), 7.68 (s, 1H),7.50-7.41 (m, 1H), 7.29-7.20 (m, 1H), 7.11-7.03 (m, 1H), 4.24-4.16 (m,1H), 4.22 (s, 2H), 3.91 (d, 1H, J = 13.9 Hz), 3.07 (s, 3H), 2.89 (s,6H), 1.92 (s, 3H). 153

HCl ¹H-NMR (DMSO-d₆) δ: 12.64 (br s, 1H), 8.53 (s, 1H), 8.34-8.23 (m,1H), 7.68 (s, 1H),7.50-7.40 (m, 1H), 7.30-7.20 (m, 1H), 7.13-7.02 (m,1H) 4.23 (s, 2H), 4.12 (d, 1H, J = 14.1 Hz), 4.01 (d, 1H, J = 14.1 Hz),3.17-2.97 (m, 2H), 3.03 (s, 3H), 1.87 (s, 3H), 0.99 (t, 3H, J = 7.4 Hz).154

HCl ¹H-NMR (DMSO-d₆) δ: 12.32 (s, 1H), 8.79 (s, 1H), 7.58-7.50 (m, 1H),7.32-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.60 (d, 1H, J = 13.0 Hz), 4.55(sep, 1H, J = 6.8 Hz), 4.48 (s, 2H), 4.35 (dd, 1H, J = 13.0, 3.0 Hz),4.27-4.20 (m, 1H), 3.26 (dd, 1H, J = 13.7, 10.5 Hz), 2.99 (dd, 1H, J =13.7, 3.0 Hz), 2.87 (s, 3H), 2.84 (s, 3H), 1.30 (d, 6H, J = 6.8 Hz).

TABLE 1-44 No. structural formula salt ¹H-NMR 155

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8.82 (s, 1H), 7.52-7.37 (m,2H), 7.27-7.20 (m, 1H), 4.99-4.91 (m, 1H), 4.77 (sep, 1H, J = 6.9 Hz),4.49 (s, 2H), 3.84 (dd, 1H, J = 13.7, 4.0 Hz), 3.79-3.69 (m, 2H), 3.64(dd, 1H, J = 10.5, 7.7 Hz), 3.58-3.45 (m, 2H), 3.34 (t, 2H, J = 4.6 Hz),3.11 (s, 3H), 1.17 (d, 3H, J = 6.9 Hz), 1.16 (d, 3H, J = 6.9 Hz). 156

HCl ¹H-NMR (DMSO-d₆) δ: 8.84 (s, 1H), 7.58-7.50 (m, 1H), 7.33-7.25 (m,1H), 7.15-7.08 (m, 1H), 4.62-4.53 (m, 1H), 4.51-4.45 (m, 3H), 4.32 (dd,1H, J = 13.1, 3.4 Hz), 4.26-4.18 (m, 1H), 1.27 (d, 3H, J = 6.9 Hz), 1.26(d, 3H, J = 6.9 Hz), 1.21 (d, 3H, J = 6.4 Hz). 157

HCl ¹H-NMR (DMSO-d₆) δ: 12.96 (s, 1H), 8.56 (s, 1H), 7.53-7.19 (m, 3H),4.80-4.66 (m, 1H), 4.50 (s, 2H), 4.15 (d, 1H, J = 14.3 Hz), 3.82 (d, 1H,J = 14.3 Hz), 3.09-2.83 (m, 6H), 2.04 (s, 3H), 1.18 (d, 3H, J = 7.1 Hz),1.11 (d, 3H, J = 7.1 Hz). 158

HCl ¹H-NMR (DMSO-d₆) δ: 12.35 (s, 1H), 8.75 (s, 1H), 7.57-7.49 (m, 2H),7.32-7.25 (m, 1H), 7.15- 7.08 (m, 1H), 4.61-4.53 (m, 2H), 4.49 (s, 2H),4.40-4.33 (m, 1H), 4.00-3.93 (m, 1H), 3.21-3.12 (m, 1H), 3.02-2.92 (m,1H), 2.90 (s, 3H), 1.30 (d, 3H, J = 6.7 Hz), 1.28 (d, 3H, J = 6.7 Hz).

TABLE 1-45 structural No. formula salt ¹H-NMR 159

HCl ¹H-NMR (DMSO-d₆) δ: 12.39 (br s, 1H), 8.83 (s, 1H), 7.58-7.49 (m,1H), 7.32-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.56 (sep, 1H, J = 6.7 Hz),4.49 (s, 2H), 4.42-4.28 (m, 2H), 4.26-4.18 (m, 1H), 3.41-3.36 (m, 2H),3.04 (s, 3H), 2.83 (t, 1H, J = 6.7 Hz), 1.34 (d, 3H, J = 6.7 Hz), 1.29(d, 3H, J = 6.7 Hz), 1.00 (d, 3H, J = 6.7 Hz), 0.99 (d, 3H, J = 6.7 Hz).160

HCl ¹H-NMR (DMSO-d₆) δ: 12.67 (br s, 1H), 8.53 (s, 1H), 8.12-8.02 (m,1H), 7.67 (s, 1H), 7.49-7.40 (m, 1H), 7.29-7.20 (m, 1H), 7.12-7.02 (m,1H), 4.22 (s, 2H), 4.07 (d, 1H, J = 14.1 Hz), 3.99 (d, 1H, J = 14.1 Hz),3.03 (s, 3H), 2.60 (d, 3H, J = 4.6 Hz), 1.86 (s, 3H). 161

HCl ¹H-NMR (DMSO-d₆) δ: 12.76 (br s, 1H), 8.41 (s, 1H), 7.66 (s, 1H),7.50-7.40 (m, 1H), 7.29-7.20 (m, 1H), 7.12-7.03 (m, 1H), 4.22 (s, 2H),4.17 (d, 1H, J = 13.9 Hz), 3.91 (d, 1H, J = 13.9 Hz), 3.46-3.17 (m, 2H),3.06 (s, 3H), 2.84 (s, 3H), 1.90 (s, 3H), 0.99 (t, 3H, J = 7.4 Hz). 162

HCl ¹H-NMR (DMSO-d₆) δ: 12.71 (br s, 1H), 8.52 (s, 1H), 8.31-8.22 (m,1H), 7.67 (s, 1H), 7.50-7.39 (m, 1H), 7.31-7.19 (m, 1H), 7.13-7.03 (m,1H), 4.22 (s, 2H), 4.14 (d, 1H, J = 13.7 Hz), 3.99 (d, 1H, J = 13.7 Hz),3.66-3.28 (m, 2H), 3.15-3.00 (m, 2H), 1.89 (s, 3H), 1.11 (t, 3H, J = 7.4Hz), 0.99 (t, 3H, J = 7.4 Hz).

TABLE 1-46 structural No. formula salt ¹H-NMR 163

HCl ¹H-NMR (DMSO-d₆) δ: 12.34 (br s, 1H), 8.78 (s, 1H), 7.44-7.38 (m,2H), 7.22-7.15 (m, 2H), 4.55 (sep, 1H, J = 6.7 Hz), 4.47 (s, 2H), 4.43(d, 1H, J = 12.4 Hz), 4.38-4.27 (m, 1H), 4.25-4.17 (m, 1H), 3.44 (dd,1H, J = 13.3, 10.0 Hz), 3.34-3.28 (m, 1H), 3.00 (s, 3H), 1.99 (s, 3H),1.33 (d, 3H, J = 6.7 Hz), 1.29 (d, 3H, J = 6.7 Hz). 164

HCl ¹H-NMR (DMSO-d₆) δ: 8.71 (s, 1H), 7.66 (s, 1H), 7.49-7.40 (m, 1H),7.29-7.20 (m, 1H), 7.12-7.03 (m, 1H), 5.06-4.95 (m, 1H), 4.21 (s, 2H),4.04 (dd, 1H, J = 13.4, 3.5 Hz), 3.68-3.60 (m, 1H), 2.97-2.88 (m, 1H),2.88-2.82 (m, 2H), 2.87 (s, 3H), 2.79 (s, 3H), 0.96-0.83 (m, 2H),0.83-0.72 (m, 1H), 0.67-0.55 (m, 1H). 165

HCl ¹H-NMR (DMSO-d₆) δ: 8.52 (s, 1H), 7.99 (t, 1H, J = 4.9 Hz), 7.65 (s,1H), 7.49-7.40 (m, 1H), 7.29-7.20 (m, 1H), 7.12-7.03 (m, 1H), 5.00-4.89(m, 1H), 4.21 (s, 2H), 4.03 (dd, 1H, J = 13.9, 3.9 Hz), 3.58-3.50 (m,1H), 3.03-2.83 (m, 3H), 2.56 (d, 2H, J = 7.4 Hz), 1.01-0.71 (m, 4H),0.80 (t, 3H, J = 7.2 Hz). 166

HCl ¹H-NMR (DMSO-d₆) δ: 8.81 (s, 1H), 7.47-7.36 (m, 2H), 7.23-7.12 (m,2H), 5.04-4.91 (m, 1H), 4.60-4.49 (m, 1H), 4.47 (s, 2H), 3.88-3.54 (m,4H), 3.27-3.23 (m, 3H), 1.61-1.46 (m, 2H), 1.15 (d, 3H, J = 6.4 Hz),0.91-0.80 (m, 3H).

TABLE 1-47 structural No. formula salt ¹H-NMR 167

HCl ¹H-NMR (DMSO-d₆) δ: 8.81 (s, 1H), 7.46-7.38 (m, 2H), 7.23-7.14 (m,2H), 5.02-4.92 (m, 1H), 4.60-4.49 (m, 1H), 4.47 (s, 2H), 3.89-3.54 (m,4H), 3.27-3.23 (m, 3H), 1.59-1.47 (m, 2H), 1.15 (d, 3H, J = 6.4 Hz),0.91-0.80 (m, 3H). 168

HCl ¹H-NMR (DMSO-d₆) δ: 8.66 (s, 1H), 7.65 (s, 1H), 7.49-7.40 (m, 1H),7.30-7.20 (m, 1H), 7.12-7.02 (m, 1H), 4.64-4.56 (m, 1H), 4.47 (sep, 1H,J = 6.7 Hz), 4.33 (dd, 1H, J = 13.3, 3.6 Hz), 4.24-4.14 (m, 3H), 3.48(dd, 1H, J = 10.2, 4.2 Hz), 3.36 (dd, 1H, J = 10.2, 7.7 Hz), 3.21 (s,3H), 1.29 (d, 3H, J = 6.7 Hz), 1.28 (d, 3H, J = 6.7 Hz). 169

HCl ¹H-NMR (DMSO-d₆) δ: 12.96 (br s, 1H), 8.55 (s, 1H), 7.54 (td, 1H, J= 8.6, 6.6 Hz), 7.29 (ddd, 1H, J = 10.2, 9.3, 2.6 Hz), 7.11 (tdd, 1H, J= 8.6, 2.6, 0.9 Hz), 4.73 (sep, 1H, J = 6.7 Hz), 4.49 (s, 2H), 4.15 (d,1H, J = 14.4 Hz), 3.82 (d, 1H, J = 14.4 Hz), 2.95 (br s, 6H), 2.03 (s,3H), 1.18 (d, 3H, J = 6.7 Hz), 1.11 (d, 3H, J = 6.7 Hz). 170

HCl ¹H-NMR (DMSO-d₆) δ: 12.91 (br s, 1H), 8.64 (s, 1H), 7.54 (td, 1H, J= 8.8, 6.6 Hz), 7.29 (ddd, 1H, J = 10.4, 9.5, 2.8 Hz), 7.12 (tdd, 1H, J= 8.8, 2.8, 1.2 Hz), 4.70 (sep, 1H, J = 6.7 Hz), 4.49 (s, 2H), 4.14 (d,1H, J = 14.1 Hz), 3.77 (d, 1H, J = 14.1 Hz), 3.71-3.50 (br m, 2H),3.36-3.24 (br m, 1H), 3.21-3.08 (br m, 1H), 2.06 (s, 3H), 1.97-1.86 (brm, 1H), 1.83-1.59 (br m, 3H), 1.17 (d, 3H, J = 6.7 Hz), 1.08 (d, 3H, J =6.7 Hz).

TABLE 1-48 structural No. formula salt ¹H-NMR 171

HCl ¹H-NMR (DMSO-d₆) δ: 12.96 (br s, 1H), 8.55 (s, 1H), 7.54 (td, 1H, J= 8.6, 6.6 Hz), 7.29 (ddd, 1H, J = 10.2, 9.3, 2.6 Hz), 7.11 (tdd, 1H, J= 8.6, 2.6, 0.9 Hz), 4.73 (sep, 1H, J = 6.7 Hz), 4.49 (s. 2H), 4.15 (d,1H, J = 14.4 Hz), 3.82 (d, 1H, J = 14.4 Hz), 2.95 (br s, 6H), 2.03 (s,3H), 1.18 (d, 3H, J = 6.7 Hz), 1.11 (d, 3H, J = 6.7 Hz). 172

HCl ¹H-NMR (DMSO-d₆) δ: 12.91 (br s, 1H), 8.64 (s, 1H), 7.54 (td, 1H, J= 8.8, 6.6 Hz), 7.29 (ddd, 1H, J = 10.4, 9.5, 2.8 Hz), 7.12 (tdd, 1H, J= 8.8, 2.8, 1.2 Hz), 4.70 (sep, 1H, J = 6.7 Hz), 4.49 (s, 2H), 4.14 (d,1H, J = 14.1 Hz), 3.77 (d, 1H, J = 14.1 Hz), 3.71-3.50 (br m, 2H),3.36-3.24 (br m, 1H), 3.21-3.08 (br m, 1H), 2.06 (s, 3H), 1.97-1.86 (brm, 1H), 1.83-1.59 (br m, 3H), 1.17 (d, 3H, J = 6.7 Hz), 1.08 (d, 3H, J =6.7 Hz). 173

HCl ¹H-NMR (DMSO-d₆) δ: 12.93 (br s, 1H), 8.62 (s, 1H), 8.19 (t, 1H, J =5.2 Hz), 7.54 (td, 1H, J = 8.7, 6.6 Hz), 7.29 (ddd, 1H, J = 10.4, 9.3,2.6 Hz), 7.12 (tdd, 1H, J = 8.7, 2.6, 0.9 Hz), 4.71 (sep, 1H, J = 6.7Hz), 4.50 (s, 2H), 4.11 (d, 1H, J = 13.9 Hz), 3.80 (d, 1H, J = 13.9 Hz),3.18-2.98 (m, 2H), 1.96 (s, 3H), 1.15 (d, 3H, J = 6.7 Hz), 1.12 (d, 3H,J = 6.7 Hz), 1.00 (t, 3H, J = 7.2 Hz).

TABLE 1-49 structural No. formula salt ¹H-NMR 174

HCl ¹H-NMR (DMSO-d₆) δ: 12.93 (br s, 1H), 8.62 (s, 1H), 8.19 (t, 1H, J =5.2 Hz), 7.54 (td, 1H, J = 8.7, 6.6 Hz), 7.29 (ddd, 1H, J = 10.4, 9.3,2.6 Hz), 7.12 (tdd, 1H, J = 8.7, 2.6, 0.9 Hz), 4.71 (sep, 1H, J = 6.7Hz), 4.50 (s, 2H), 4.11 (d, 1H, J = 13.9 Hz), 3.80 (d, 1H, J = 13.9 Hz),3.18-2.98 (m, 2H), 1.96 (s, 3H), 1.15 (d, 3H, J = 6.7 Hz), 1.12 (d, 3H,J = 6.7 Hz), 1.00 (t, 3H, J = 7.2 Hz). 175

HCl ¹H-NMR (DMSO-d₆) δ: 8.43 (s, 1H), 7.42-7.37 (m, 2H), 7.21-7.15 (m,2H), 4.76 (sep, 1H, J = 6.9 Hz), 4.46 (s, 2H), 3.66 (s, 2H), 1.66-1.61(m, 2H), 1.13-1.18 (m, 2H), 1.16 (d, 6H, J = 6.9 Hz). 176

HCl ¹H-NMR (DMSO-d₆) δ: 8.67 (s, 1H), 7.43-7.38 (m, 2H), 7.21-7.16 (m,2H), 4.47 (s, 2H), 4.31 (s, 2H), 4.15 (sep, 1H, J = 6.9 Hz), 1.35-1.29(m, 2H), 1.32 (d, 6H, J = 6.9 Hz), 1.07-1.02 (m, 2H). 177

HCl ¹H-NMR (DMSO-d₆) δ: 12.95 (s, 1H), 8.55 (s, 1H), 7.44-7.36 (m, 2H),7.21-7.15 (m, 2H), 4.73 (sep, 1H, J = 6.7 Hz), 4.48 (s, 2H), 4.15 (d,1H, J = 14.1 Hz), 3.82 (d, 1H, J = 14.1 Hz), 3.07-2.81 (br m, 6H), 2.04(s, 3H), 1.18 (d, 3H, J = 6.7 Hz), 1.11 (d, 3H, J = 6.7 Hz).

TABLE 1-50 structural No. formula salt ¹H-NMR 178

HCl ¹H-NMR (DMSO-d₆) δ: 12.87 (s, 1H), 8.55 (s, 1H), 7.44-7.37 (m, 2H),7.22-7.14 (m, 2H), 4.48 (s, 2H), 4.15 (d, 1H, J = 13.9 Hz), 3.85 (d, 1H,J = 13.9 Hz), 2.95-2.83 (m, 1H), 2.89 (s, 6H), 1.97 (s, 3H), 0.95-0.80(m, 2H), 0.76-0.62 (m, 2H). 179

HCl ¹H-NMR (DMSO-d₆) δ: 12.90 (s, 1H), 8.65 (s, 1H), 7.45-7.38 (m, 2H),7.23-7.15 (m, 2H), 4.70 (sep, 1H, J = 6.7 Hz), 4.48 (s, 2H), 4.14 (d,1H, J = 13.9 Hz), 3.77 (d, 1H, J = 13.9 Hz), 3.72-3.62 (br m, 1H),3.36-3.23 (br m, 2H), 3.20-3.09 (br m, 1H), 2.06 (s, 3H), 1.98-1.84 (brm, 1H), 1.83-1.59 (br m, 3H), 1.17 (d, 3H, J = 6.7 Hz), 1.08 (d, 3H, J =6.7 Hz). 180

HCl ¹H-NMR (DMSO-d₆) δ: 12.92 (s, 1H), 8.62 (s, 1H), 8.17 (t, 1H, J =5.2 Hz), 7.44-7.37 (m, 2H), 7.23-7.15 (m, 2H), 4.71 (sep, 1H, J = 6.7Hz), 4.48 (s, 2H), 4.10 (d, 1H, J = 13.9 Hz), 3.80 (d, 1H, J = 13.9 Hz),3.18-2.99 (m, 2H), 1.96 (s, 3H), 1.15 (d, 3H, J = 6.7 Hz), 1.12 (d, 3H,J = 6.7 Hz), 1.01 (t, 3H, J = 7.2 Hz). 181

HCl ¹H-NMR (DMSO-d₆) δ: 12.98 (br s, 1H), 8.59 (s, 1H), 7.45-7.37 (m,2H), 7.23-7.15 (m, 2H), 4.47 (s, 2H), 4.32 (d, 1H, J = 14.4 Hz), 3.82(d, 1H, J = 14.4 Hz), 2.90 (s, 6H), 2.03 (s, 3H), 1.45 (s, 9H).

TABLE 1-51 structural No. formula salt ¹H-NMR 182

HCl ¹H-NMR (DMSO-d₆) δ: 8.91 (s, 1H), 7.44-7.38 (m, 2H), 7.22-7.15 (m,2H), 4.55 (sep, 1H, J = 6.7 Hz), 4.47 (s, 2H), 4.43-4.29 (m, 2H),4.26-4.19 (m, 1H), 3.47 (dd, 1H, J = 13.3, 4.0 Hz), 3.28 (dd, 1H, J =13.3, 10.0 Hz), 3.12 (s, 3H), 1.35 (d, 3H, J = 6.7 Hz), 1.30 (d, 3H, J =6.7 Hz), 1.20 (s, 9H). 183

HCl ¹H-NMR (DMSO-d₆) δ: 8.92 (s, 1H), 7.44-7.38 (m, 2H), 7.22-7.15 (m,2H), 4.55 (sep, 1H, J = 6.7 Hz), 4.47 (s, 2H), 4.38-4.33 (m, 2H),4.22-4.16 (m, 1H), 3.47 (dd, 1H, J = 13.5, 3.5 Hz), 3.28 (dd, 1H, J =13.5, 10.0 Hz), 3.12 (s, 3H), 1.65-1.57 (m, 2H), 1.35 (d, 3H, J = 6.7Hz), 1.30 (d, 3H, J = 6.7 Hz), 1.17 (s, 3H), 1.16 (s, 3H), 0.79 (t, 3H,J = 7.5 Hz). 184

HCl ¹H-NMR (DMSO-d₆) δ: 12.41 (br s, 1H), 8.90 (s, 1H), 7.58-7.50 (m,1H), 7.32-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.56 (sep, 1H, J = 6.6 Hz),4.49 (s, 2H), 4.41-4.29 (m, 2H), 4.27-4.18 (m, 1H), 3.48-3.44 (m, 1H),3.29 (dd, 1H, J = 13.5, 10.0 Hz), 3.12 (s, 3H), 1.35 (d, 3H, J = 6.7Hz), 1.30 (d, 3H, J = 6.7 Hz), 1.20 (s, 9H). 185

HCl ¹H-NMR (DMSO-d₆) δ: 12.90 (br s, 1H), 8.63 (s, 1H), 8.12 (q, 1H, J =4.4 Hz), 7.45-7.37 (m, 2H), 7.23-7.15 (m, 2H), 4.70 (sep, 1H, J = 6.7Hz), 4.48 (s, 2H), 4.08 (d, 1H, J = 13.9 Hz), 3.80 (d, 1H, J = 13.9 Hz),2.59 (d, 3H, J = 4.4 Hz), 1.97 (s, 3H), 1.15 (d, 3H, J = 6.7 Hz), 1.09(d, 3H, J = 6.7 Hz).

TABLE 1-52 structural No. formula salt ¹H-NMR 186

HCl ¹H-NMR (DMSO-d₆) δ: 12.93 (br s, 1H), 8.64 (s, 1H), 8.09 (t, 1H, J =6.0 Hz), 7.43-7.38 (m, 2H), 7.22-7.15 (m, 2H), 4.69 (sep, 1H, J = 6.7Hz), 4.48 (s, 2H), 4.14 (d, 1H, J = 13.9 Hz), 3.79 (d, 1H, J = 13.9 Hz),3.10-3.01 (m, 1H), 2.71-2.62 (m, 1H), 1.97 (s, 3H), 1.75-1.61 (m, 1H),1.15 (d, 3H, J = 6.7 Hz), 1.11 (d, 3H, J = 6.7 Hz), 0.79 (d, 6H, J = 6.7Hz). 187

HCl ¹H-NMR (DMSO-d₆) δ: 12.85 (br s, 1H), 8.62 (s, 1H), 8.19 (t, 1H, J =5.2 Hz), 7.45-7.36 (m, 2H), 7.22-7.15 (m, 2H), 4.48 (s, 2H), 4.00 (d,1H, J = 13.7 Hz), 3.96 (d, 1H, J = 13.7 Hz), 3.11-3.02 (m, 2H), 2.88(sep, 1H, J = 3.9 Hz), 1.92 (s, 3H), 0.98 (t, 3H, J = 7.0 Hz), 0.96-0.89(m, 1H), 0.85-0.69 (m, 2H), 0.65-0.56 (m, 1H). 188

HCl ¹H-NMR (DMSO-d₆) δ: 12.93 (br s, 1H), 8.69 (s, 1H), 7.45-7.39 (m,2H), 7.22-7.15 (m, 2H), 4.48 (s, 2H), 4.32 (d, 1H, J = 13.9 Hz), 3.77(d, 1H, J = 13.9 Hz), 3.44-3.23 (br m, 4H), 2.01 (s, 3H), 1.92-1.54 (brm, 4H), 1.44 (s, 9H). 189

HCl ¹H-NMR (DMSO-d₆) δ: 12.98 (br s, 1H), 8.59 (s, 1H), 8.19 (t, 1H, J =7.0 Hz), 7.44-7.37 (m, 2H), 7.23-7.15 (m, 2H), 4.48 (s, 2H), 4.23 (d,1H, J = 13.7 Hz), 3.83 (d, 1H, J = 13.7 Hz), 3.10 (dq, 2H, J = 7.0, 7.0Hz), 1.94 (s, 3H), 1.45 (s, 9H), 1.02 (t, 3H, J = 7.0 Hz).

TABLE 1-53 structural No. formula salt ¹H-NMR 190

HCl ¹H-NMR (DMSO-d₆) δ: 12.90 (br s, 1H), 8.62 (s, 1H), 8.10 (q, 1H, J =4.4 Hz), 7.53 (td, 1H, J = 8.6, 6.5 Hz), 7.28 (ddd, 1H, J = 10.2, 9.5,2.6 Hz), 7.11 (tdd, 1H, J = 8.6, 2.6, 1.1 Hz), 4.69 (sep, 1H, J = 6.7Hz), 4.49 (s, 2H), 4.06 (d, 1H, J = 13.9 Hz), 3.78 (d, 1H, J = 13.9 Hz),2.58 (d, 3H, J = 4.4 Hz), 1.95 (s, 3H), 1.13 (d, 3H, J = 6.7 Hz), 1.08(d, 3H, J = 6.7 Hz). 191

HCl ¹H-NMR (DMSO-d₆) δ: 12.90 (br s, 1H), 8.62 (s, 1H), 8.10 (q, 1H, J =4.4 Hz), 7.53 (td, 1H, J = 8.6, 6.5 Hz), 7.28 (ddd, 1H, J = 10.2, 9.5,2.6 Hz), 7.11 (tdd, 1H, J = 8.6, 2.6, 1.1 Hz), 4.69 (sep, 1H, J = 6.7Hz), 4.49 (s, 2H), 4.06 (d, 1H, J = 13.9 Hz), 3.78 (d, 1H, J = 13.9 Hz),2.58 (d, 3H, J = 4.4 Hz), 1.95 (s, 3H), 1.13 (d, 3H, J = 6.7 Hz), 1.08(d, 3H, J = 6.7 Hz). 192

HCl ¹H-NMR (DMSO-d₆) δ: 12.88 (br s, 1H), 8.82 (s, 1H), 7.45-7.39 (m,2H), 7.22-7.16 (m, 2H), 4.77 (sep, 1H, J = 6.9 Hz), 4.63-4.59 (m, 1H),4.47 (s, 2H), 3.89-3.82 (m, 2H), 1.27 (d, 3H, J = 6.9 Hz), 1.19 (d, 3H,J = 6.9 Hz), 0.96 (s, 9H). 193

HCl ¹H-NMR (DMSO-d₆) δ: 12.88 (br s, 1H), 8.82 (s, 1H), 7.45-7.39 (m,2H), 7.22-7.16 (m, 2H), 4.77 (sep, 1H, J = 6.9 Hz), 4.63-4.59 (m, 1H),4.47 (s, 2H), 3.89-3.83 (m, 2H), 1.28 (d, 3H, J = 6.9 Hz), 1.19 (d, 3H,J = 6.9 Hz), 0.96 (s, 9H).

TABLE 1-54 structural No. formula salt ¹H-NMR 194

HCl ¹H-NMR (DMSO-d₆) δ: 12.76 (br s, 1H), 8.90 (s, 1H), 7.45-7.39 (m,2H), 7.22-7.16 (m, 2H), 4.79-4.79 (sep, 1H, J = 6.7 Hz), 4.50-4.43 (m,1H), 4.47 (s, 2H), 3.86-3.78 (m, 2H), 2.03-1.92 (m, 1H), 1.20 (d, 3H, J= 6.7 Hz), 1.18 (d, 3H, J = 6.7 Hz), 1.04 (d, 3H, J = 6.7 Hz), 0.69 (d,3H, J = 6.7 Hz). 195

HCl ¹H-NMR (DMSO-d₆) δ: 12.49 (br s, 1H), 8.85 (s, 1H), 7.44-7.38 (m,2H), 7.22-7.15 (m, 2H), 4.68 (dd, 1H, J = 13.5, 1.3 Hz), 4.61-4.49 (m,1H), 4.47 (s, 2H), 4.41 (dd, 1H, J = 13.5, 4.0 Hz), 4.31-4.25 (m, 1H),3.43 (dd, 1H, J = 10.6, 5.0 Hz), 3.39 (dd, 1H, J = 10.6, 6.8 Hz), 3.21(s, 3H), 2.38-2.11 (m, 4H), 1.77-1.64 (m, 2H). 196

HCl ¹H-NMR (DMSO-d₆) δ: 12.49 (br s, 1H), 8.85 (s, 1H), 7.44-7.37 (m,2H), 7.22-7.15 (m, 2H), 4.65 (dd, 1H, J = 13.7, 1.5 Hz), 4.47 (s, 2H),4.44-4.34 (m, 2H), 4.20-4.13 (m, 1H), 3.47 (dd, 1H, J = 10.4, 4.6 Hz),3.41 (dd, 1H, J = 10.4, 7.3 Hz), 3.21 (s, 3H), 1.95-1.72 (m, 6H),1.63-1.49 (m, 2H). 197

HCl ¹H-NMR (DMSO-d₆) δ: 13.29 (br s, 1H), 8.52 (s, 1H), 7.60-7.50 (m,1H), 7.36-7.25 (m, 1H), 7.17-7.08 (m, 1H), 4.86-4.73 (m, 1H), 4.49 (s,2H), 3.91-3.64 (m, 4H), 2.82 (s, 3H), 1.81 (s, 3H), 1.71 (s, 3H), 1.23(d, 3H, J = 6.7 Hz), 1.17 (d, 3H, J = 7.0 Hz).

TABLE 1-55 structural No. formula salt ¹H-NMR 198

HCl ¹H-NMR (DMSO-d₆) δ: 8.88 (s, 1H), 7.45-7.37 (m, 2H), 7.23-7.15 (m,2H), 4.70 (d, 1H, J = 13.0 Hz), 4.47 (s, 2H), 4.39-4.27 (m, 2H),3.73-3.61 (m, 2H), 3.49-3.41 (m, 1H), 3.22 (s, 3H), 1.34 (d, 3H, J = 6.7Hz), 1.26-1.13 (m, 1H), 0.69-0.60 (m, 1H), 0.54-0.45 (m, 1H), 0.42-0.27(m, 2H). 199

HCl ¹H-NMR (DMSO-d₆) δ: 12.87 (s, 1H), 8.56 (s, 1H), 7.45-7.37 (m, 2H),7.23-7.15 (m, 2H), 4.48 (s, 2H), 4.21 (d, 1H, J = 13.9 Hz), 3.98 (d, 1H,J = 13.9 Hz), 3.53 (q, 2H, J = 7.0 Hz), 2.50 (s, 6H), 2.01 (s, 3H), 1.11(t, 3H, J = 7.0 Hz). 200

HCl ¹H-NMR (DMSO-d₆) δ: 12.81 (br s, 1H), 8.67 (s, 1H), 7.45-7.39 (m,2H), 7.22-7.15 (m, 2H), 4.48 (s, 2H), 4.19 (d, 1H, J = 13.9 Hz), 3.96(d, 1H, J = 13.9 Hz), 3.59-3.25 (br m, 3H), 3.53 (dq, 1H, J = 14.0, 7.0Hz), 3.49 (dq, 1H, J = 14.0, 7.0 Hz), 3.12-2.96 (br m, 1H), 2.01 (s,3H), 1.96-1.48 (m, 4H), 1.09 (t, 3H, J = 7.0 Hz). 201

HCl ¹H-NMR (DMSO-d₆) δ: 12.81 (br s, 1H), 8.62 (s, 1H), 8.26 (t, 1H, J =5.6 Hz), 7.44-7.38 (m, 2H), 7.22-7.15 (m, 2H), 4.48 (s, 2H), 4.13 (d,1H, J = 13.9 Hz), 4.01 (d, 1H, J = 13.9 Hz), 3.62 (dq, 1H, J = 14.2, 7.1Hz), 3.36 (dq, 1H, J = 14.2, 7.1 Hz), 3.14-3.04 (m, 2H), 1.93 (s, 3H),1.11 (t, 3H, J = 7.1 Hz), 1.00 (t, 3H, J = 7.1 Hz).

TABLE 1-56 structural No. formula salt ¹H-NMR 202

HCl ¹H-NMR (DMSO-d₆) δ: 13.00 (br s, 1H), 8.57 (s, 1H), 7.45-7.37 (m,2H), 7.22-7.15 (m, 2H), 4.72 (sep, 1H, J = 6.7 Hz), 4.48 (s, 2H), 4.18(d, 1H, J = 14.4 Hz), 3.81 (d, 1H, J = 14.4 Hz), 3.64 (br s, 3H), 3.42(t, 2H, J = 5.3 Hz), 3.20 (s, 3H), 3.05-2.92 (br m, 2H), 2.02 (s, 3H),1.18 (d, 3H, J = 6.7 Hz), 1.13 (d, 3H, J = 6.7 Hz). 203

HCl ¹H-NMR (DMSO-d₆) δ: 13.06 (br s, 1H), 8.52 (s, 1H), 7.46-7.38 (m,2H), 7.23-7.15 (m, 2H), 4.75 (sep, 1H, J = 6.7 Hz), 4.48 (s, 2H), 4.05(d, 1H, J = 14.4 Hz), 3.84 (d, 1H, J = 14.4 Hz), 3.62-3.48 (br m, 8H),1.98 (s, 3H), 1.18 (d, 3H, J = 6.7 Hz), 1.16 (d, 3H, J = 6.7 Hz). 204

HCl ¹H-NMR (DMSO-d₆) δ: 12.95 (br s, 1H), 8.68-8.61 (m, 1H), 7.45-7.38(m, 2H), 7.22-7.15 (m, 2H), 4.69 (sep, 1H, J = 6.7 Hz), 4.48 (s, 2H),4.23-4.15 (br m, 1H), 4.11 (d, 1H, J = 13.9 Hz), 3.76 (d, 1H, J = 13.9Hz), 3.69-3.59 (br m, 1H), 3.46-3.36 (br m, 2H), 3.30-2.88 (br m, 1H),2.09-2.00 (m, 3H), 2.02-1.55 (br m, 2H), 1.21-1.06 (m, 6H). 205

HCl ¹H-NMR (DMSO-d₆) δ: 12.91 (br s, 1H), 8.71-8.61 (m, 1H), 7.46-7.37(m, 2H), 7.24-7.14 (m, 2H), 4.69 (sep, 1H, J = 6.7 Hz), 4.48 (s, 2H),4.33-4.13 (br m, 2H), 4.08 (d, 1H, J = 13.9 Hz), 3.77 (d, 1H, J = 13.9Hz), 3.51-3.15 (br m, 3H), 2.14-2.01 (m, 3H), 1.89-1.61 (br m, 2H),1.21-1.02 (m, 6H).

TABLE 1-57 structural No. formula salt ¹H-NMR 206

HCl ¹H-NMR (DMSO-d₆) δ: 8.87 (s, 1H), 7.44-7.38 (m, 2H), 7.23-7.15 (m,2H), 4.72 (d, 1H, J = 12.3 Hz), 4.47 (s, 2H), 4.43-4.33 (m, 2H),3.67-3.58 (m, 1H), 3.57-3.51 (m, 1H), 3.47-3.40 (m, 1H), 3.22 (s, 3H),1.34 (d, 3H, J = 6.7 Hz), 1.31-1.21 (m, 1H), 0.68-0.59 (m, 1H),0.54-0.46 (m, 1H), 0.44-0.36 (m, 1H), 0.32-0.24 (m, 1H). 207

HCl ¹H-NMR (DMSO-d₆) δ: 13.31 (br s, 1H), 8.48 (s, 1H), 7.59-7.49 (m,1H), 7.38-7.22 (m, 1H), 7.20-7.05 (m, 1H), 4.87-4.73 (m, 1H), 4.48 (s,2H), 4.02-3.86 (m, 1H), 3.80 (d, 1H, J = 13.7 Hz), 3.71 (d, 1H, J = 13.7Hz), 3.47-3.32 (m, 1H), 2.85 (s, 3H), 2.17-2.04 (m, 2H), 1.71 (s, 3H),1.23 (d, 3H, J = 7.0 Hz), 1.17 (d, 3H, J = 7.0 Hz), 0.65 (t, 3H, J = 7.4Hz). 208

HCl ¹H-NMR (DMSO-d₆) δ: 12.93 (br s, 1H), 8.72 (s, 1H), 7.45-7.38 (m,2H), 7.23-7.15 (m, 2H), 4.69 (sep, 1H, J = 6.7 Hz), 4.48 (s, 2H),4.44-4.27 (br m, 2H), 4.11-3.82 (br m, 2H), 4.02 (d, 1H, J = 13.9 Hz),3.72 (d, 1H, J = 13.9 Hz), 3.64-3.40 (br m, 1H), 1.99 (s, 3H), 1.16 (d,3H, J = 6.7 Hz), 1.12 (d, 3H, J = 6.7 Hz).

TABLE 1-58 structural No. formula salt ¹H-NMR 209

HCl ¹H-NMR (DMSO-d₆) δ: 12.89 (br s, 1H), 8.71 (s, 1H), 7.45-7.38 (m,2H), 7.22-7.15 (m, 2H), 4.70 (sep, 1H, J = 6.8 Hz), 4.48 (s, 2H),4.22-3.90 (br m, 4H), 4.00 (d, 1H, J = 13.9 Hz), 3.74-3.57 (br m, 1H),3.74 (d, 1H, J = 13.9 Hz), 3.14 (s, 3H), 2.00 (s, 3H), 1.19-1.09 (m,6H). 210

HCl ¹H-NMR (DMSO-d₆) δ: 13.30 (s, 1H), 8.60 (s, 1H), 7.56-7.50 (m, 1H),7.35-7.25 (m, 1H), 7.13-7.08 (m, 1H), 4.80-4.74 (m, 1H), 4.47 (s, 2H),3.75 (s, 2H), 3.48-3.30 (m, 2H), 2.84 (s, 3H), 2.57 (s, 3H), 1.74 (s,3H), 1.24 (d, 3H, J = 6.7 Hz), 1.15 (d, 3H, J = 6.7 Hz). 211

HCl ¹H-NMR (DMSO-d₆) δ: 12.91 (s, 0.5H), 12.86 (s, 0.5H), 8.68 (s,0.5H), 8.60 (s, 0.5H), 7.42-7.38 (m, 2H), 7.20-7.15 (m, 2H), 4.72-4.65(m, 1H), 4.47 (s, 2H), 4.16 (d, 0.5H, J = 13.7 Hz), 4.08 (d, 0.5H, J =13.7 Hz), 4.00-3.98 (m, 0.5H), 3.86-3.84 (m, 0.5H) 3.81-3.74 (m, 2H),3.51-3.33 (m, 3H), 3.17 (s, 3H), 2.54-2.49 (m, 2H), 2.07 (s, 3H), 1.15(d, 3H, J = 6.7 Hz), 1.05 (d, 3H, J = 6.7 Hz).

TABLE 1-59 structural No. formula salt ¹H-NMR 212

HCl ¹H-NMR (DMSO-d₆) δ: 12.94 (s, 1H), 8.66 (s, 0.5H), 8.62 (s, 0.5H),7.42-7.38 (m, 2H), 7.20-7.15 (m, 2H), 4.70-4.65 (m, 1H), 4.47 (s, 2H),4.11-4.06 (m, 1H), 3.93-3.90 (m, 1H), 3.87-3.84 (m, 1H), 3.81-3.75 (m,1H) 3.69-3.65 (m, 1H), 3.62-3.45 (m, 1H), 3.17 (s, 1.5H), 3.15 (s,1.5H), 3.10-3.06 (m, 1H), 2.07 (s, 1.5H), 2.05 (s, 1.5H), 1.99-1.96 (m,1H), 1.79-1.76 (m, 1H), 1.16 (d, 3H, J = 6.7 Hz), 1.06 (d, 3H, J = 6.7Hz). 213

HCl ¹H-NMR (DMSO-d₆) δ: 12.77 (br s, 1H), 8.55 (s, 0.5H), 8.48 (s,0.5H), 7.67 (s, 1H), 7.34-7.29 (m, 2H), 7.17-7.11 (m, 2H), 4.71-4.65 (m,1H), 4.25-4.04 (m, 1H), 4.20 (s, 2H), 3.98-3.86 (m, 0.5H), 3.85-3.84 (m,0.5H), 3.78-3.68 (m, 2H), 3.50-3.25 (m, 2H), 3.17 (s, 1.5H), 3.15 (s,1.5H), 2.54-2.49 (m, 1H), 2.02 (s, 3H), 1.91-1.85 (m, 1H), 1.78-1.71 (m,1H), 1.15 (d, 3H, J = 6.7 Hz), 1.05 (d, 3H, J = 6.7 Hz). 214

HCl ¹H-NMR (DMSO-d₆) δ: 12.84 (br s, 1H), 8.54 (s, 0.5H), 8.50 (s,0.5H), 7.68 (s, 1H), 7.34-7.31 (m, 2H), 7.17-7.11 (m, 2H), 4.71-4.65 (m,1H), 4.20 (s, 2H), 4.07 (dd, 1H, J = 13.9, 5.3 Hz), 3.90-3.85 (m, 1H),3.75 (dd, 1H, J = 13.9, 7.4 Hz), 3.59-3.36 (m, 3H), 3.15 (s, 3H),2.54-2.49 (m, 1H), 2.02 (s, 1.5H), 1.99 (s, 1.5H), 1.99-1.97 (m, 1H),1.78-1.71 (m, 1H), 1.16 (d, 3H, J = 6.7 Hz), 1.08 (d, 3H, J = 6.7 Hz).

TABLE 1-60 structural No. formula salt ¹H-NMR 215

HCl ¹H-NMR (DMSO-d₆) δ: 13.20 (br s, 1H), 8.44 (s, 1H), 7.67 (s, 1H),7.35-7.31 (m, 2H), 7.16-7.11 (m, 2H), 4.81-4.74 (m, 1H), 4.19 (s, 2H),3.79-3.65 (m, 3H), 3.57 (d, 1H, J = 14.4 Hz), 2.74 (s, 3H), 1.81 (s,3H), 1.66 (s, 3H), 1.21 (d, 3H, J = 6.7 Hz), 1.15 (d, 3H, J = 6.7 Hz).216

HCl ¹H-NMR (DMSO-d₆) δ: 12.60 (br s, 1H), 8.63 (s, 1H), 7.66 (s, 1H),7.35-7.30 (m, 2H), 7.17-7.11 (m, 2H), 4.89-4.85 (m, 1H), 4.19 (s, 2H),4.08 (dd, 1H, J = 13.7, 4.2 Hz), 3.81 (d, 1H, J = 13.7 Hz), 3.57 (dd,1H, J = 10.5, 5.7 Hz), 3.66 (dd, 1H, J = 10.5, 7.9 Hz), 3.56-3.39 (m,3H), 3.33-3.27 (m, 3H), 3.10 (s, 3H), 1.10-1.04 (m, 1H), 0.55-0.46 (m,2H), 0.36-0.26 (m, 2H). 217

HCl ¹H-NMR (DMSO-d₆) δ: 12.30 (br s, 1H), 8.65 (s, 1H), 7.66 (s, 1H),7.34-7.30 (m, 2H), 7.16-7.11 (m, 2H), 4.60 (d, 1H, J = 13.2 Hz), 4.42(dd, 1H, J = 13.2, 3.9 Hz), 4.24-4.19 (m, 1H), 4.19 (s, 2H), 3.67 (dd,1H, J = 14.2, 7.0 Hz), 3.55 (dd, 1H, J = 10.3, 4.8 Hz), 3.47 (dd, 1H, J= 10.3, 7.0 Hz), 3.20 (s, 3H), 3.19 (dd, 1H, J = 14.2, 7.4 Hz),1.18-1.12 (m, 1H), 0.55-0.46 (m, 2H), 0.41-0.37 (m, 1H), 0.31-0.28 (m,1H).

TABLE 1-61 structural No. formula salt ¹H-NMR 218

HCl ¹H-NMR (DMSO-d₆) δ: 12.30 (br s, 1H), 8.65 (s, 1H), 7.66 (s, 1H),7.34-7.31 (m, 2H), 7.16-7.11 (m, 2H), 4.61 (d, 1H, J = 13.5 Hz), 4.42(dd, 1H, J = 13.5, 4.2 Hz), 4.24-4.19 (m, 1H), 4.19 (s, 2H), 3.67 (dd,1H, J = 14.0, 7.1 Hz), 3.60 (dd, 1H, J = 10.3, 4.2 Hz), 3.52 (dd, 1H, J= 10.3, 6.4 Hz), 3.42-3.30 (m, 2H), 3.20 (dd, 1H, J = 14.0, 7.0 Hz),1.16-1.11 (m, 1H), 0.95 (t, 3H, J = 7.0 Hz), 0.56-0.46 (m, 2H),0.41-0.37 (m, 1H), 0.31-0.27 (m, 1H). 219

HCl ¹H-NMR (DMSO-d₆) δ : 12.79 (br s, 1H), 8.78 (s, 1H), 7.35 (dd, 1H, J= 8.4, 7.0 Hz), 6.93 (dd, 1H, J = 11.4, 2.6 Hz), 6.74 (td, 1H, J = 8.4,2.6 Hz), 4.97-4.93 (m, 1H), 4.79-4.72 (m, 1H), 4.33 (s, 2H), 406 (q, 2H,J = 7.0 Hz), 3.79-3.65 (m, 2H), 3.61 (dd, 1H, J = 10.3, 5.7 Hz), 3.55(dd, 1H, J = 10.3, 7.7 Hz), 3.23 (s, 3H), 1.31 (t, 3H, J = 7.0 Hz), 1.15(d, 3H, J = 2.3 Hz), 1.14 (d, 3H, J = 2.3 Hz). 220

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (s, 1H), 8.76 (s, 1H), 6.93-6.87 (m, 2H),4.97-4.93 (m, 1H), 4.79-4.72 (m, 1H), 4.33 (s, 2H), 3.85 (s, 3H),3.84-3.72 (m, 2H), 3.61 (dd, 1H, J = 10.3, 5.7 Hz), 3.55 (dd, 1H, J =10.3, 7.8 Hz), 3.23 (s, 3H), 1.15 (d, 3H, J = 2.3 Hz), 1.14 (d, 3H, J =2.3 Hz).

TABLE 1-62 structural No. formula salt ¹H-NMR 221

HCl ¹H-NMR (DMSO-d₆) δ: 12.50 (br s, 1H), 9.02 (s, 1H), 7.43-7.39 (m,2H), 7.21-7.16 (m, 2H), 4.76 (d, 1H, J = 13.3 Hz), 4.47 (s, 2H), 4.30(dd, 1H, J = 13.3, 4.6 Hz), 4.21-4.14 (m, 1H), 3.83 (br t, 1H, J = 4.6Hz), 2.04-1.99 (m, 1H), 1.39 (d, 3H, J = 6.9 Hz), 1.35 (d, 3H, J = 6.9Hz), 1.05 (d, 3H, J = 6.9 Hz), 0.64 (d, 3H, J = 6.9 Hz). 222

HCl ¹H-NMR (DMSO-d₆) δ: 12.30 (br s, 1H), 8.65 (s, 1H), 7.67 (s, 1H),7.35-7.31 (m, 2H), 7.18-7.13 (m, 2H), 4.59 (br d, 1H, J = 13.3 Hz), 4.41(dd, 1H, J = 13.3, 4.1 Hz), 4.20 (s, 2H), 4.12-4.09 (m, 1H), 3.89-3.84(m, 1H), 3.58-3.50 (m, 2H), 3.41-3.34 (m, 2H), 3.29-3.24 (m, 1H), 1.20(t, 3H, J = 7.2 Hz), 0.97 (t, 3H, J = 7.0 Hz). 223

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (m, 1H), 8.59 (s, 1H), 7.69 (s, 1H),7.34-7.30 (m, 2H), 7.17-7.11 (m, 2H), 4.72-4.65 (m, 1H), 4.20 (s, 2H),4.20-4.13 (m, 1H), 4.00 (d, 1H, J = 13.5 Hz), 3.86-3.80 (m, 2H),3.75-3.66 (m, 2H), 2.12-2.03 (m, 2H), 1.93 (s, 3H), 1.14 (d, 3H, J = 6.7Hz), 1.12 (d, 3H, J = 6.7 Hz). 224

HCl ¹H-NMR (DMSO-d₆) δ: 12.55 (br s, 1H), 9.02 (s, 1H), 7.43-7.39 (m,2H), 7.21-7.16 (m, 2H), 4.76 (d, 1H, J = 13.3 Hz), 4.47 (s, 2H), 4.30(dd, 1H, J = 13.3, 4.6 Hz), 4.21-4.14 (m, 1H), 3.83 (br t, 1H, J = 4.6Hz), 2.04-1.99 (m, 1H), 1.39 (d, 3H, J = 6.9 Hz), 1.35 (d, 3H, J = 6.9Hz), 1.05 (d, 3H, J = 6.9 Hz), 0.64 (d, 3H, J = 6.9 Hz).

TABLE 1-63 structural No. formula salt ¹H-NMR 225

HCl ¹H-NMR (DMSO-d₆) ι: 12.78 (s, 1H), 8.52 (s, 1H), 7.67 (s, 1H),7.34-7.30 (m, 2H), 7.16-7.12 (m, 2H), 4.72-4.66 (m, 1H), 4.19 (s, 2H),4.11 (d, 1H, J = 13.9 Hz), 3.74 (d, 1H, J = 13.9 Hz), 3.41-3.25 (m, 1H),3.13-3.06 (m, 1H), 3.81-3.74 (m, 2H), 2.00 (s, 3H), 1.92-1.84 (m, 1H),1.75-1.61 (m, 3H), 1.15 (d, 3H, J = 6.7 Hz), 1.07 (d, 3H, J = 6.7 Hz).226

HCl ¹H-NMR (DMSO-d₆) δ: 12.81 (br s, 1H), 8.51 (s, 1H), 8.20 (br t, 1H,J = 5.5 Hz), 7.67 (s, 1H), 7.34-7.30 (m, 2H), 7.16-7.11 (m, 2H),4.73-4.66 (m, 1H), 4.20 (s, 2H), 4.11 (d, 1H, J = 13.7 Hz), 3.77 (d, 1H,J = 13.7 Hz), 3.13-2.99 (m, 2H), 1.92 (s, 3H), 1.14 (d, 3H, J = 6.7 Hz),1.10 (d, 3H, J = 6.7 Hz), 0.99 (t, 3H, J = 7.2 Hz). 227

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (br s, 1H), 8.54 (s, 1H), 8.22 (d, 1H, J =4.4 Hz), 7.69 (s, 1H), 7.34-7.30 (m, 2H), 7.16-7.12 (m, 2H), 4.73-4.66(m, 1H), 4.20 (s, 2H), 4.13 (d, 1H, J = 13.7 Hz), 3.78 (d, 1H, J = 13.7Hz), 2.57 (d, 3H, J = 4.4 Hz), 1.93 (s, 3H), 1.13 (d, 3H, J = 7.0 Hz),1.08 (d, 3H, J = 7.0 Hz).

TABLE 1-64 structural No. formula salt ¹H-NMR 228

HCl ¹H-NMR (DMSO-d₆) δ: 12.85 (br s, 1H), 8.81 (s, 1H), 7.48-7.46 (m,1H), 7.42-7.33 (m, 3H), 4.98-4.96 (m, 1H), 4.80-4.73 (m, 1H), 4.50 (s,2H), 3.84 (dd, 1H, J = 13.8, 4.1 Hz), 3.75 (br d, 1H, J = 13.8 Hz), 3.63(dd, 1H, J = 10.4, 5.7 Hz), 3.57 (dd, 1H, J = 10.4, 7.5 Hz), 3.25 (s,3H), 1.17 (d, 3H, J = 2.0 Hz), 1.15 (d, 3H, J = 2.0 Hz). 229

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8.80 (s, 1H), 7.51 (t, 1H, J =8.3 Hz), 7.48 (dd, 1H, J = 8.3, 2.0 Hz), 7.32 (dd, 1H, J = 8.3, 2.0 Hz),5.00-4.95 (m, 1H), 4.80-4.74 (m, 1H), 4.50 (s, 2H), 3.84 (dd, 1H, J =13.7, 4.0 Hz), 3.75 (dd, 1H, J = 13.7, 1.6 Hz), 3.62 (dd, 1H, J = 10.3,5.8 Hz), 3.57 (dd, 1H, J = 10.3, 7.7 Hz), 3.25 (s, 3H), 1.17 (d, 3H, J =2.0 Hz), 1.15 (d, 3H, J = 2.0 Hz). 230

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8.79 (s, 1H), 7.66 (dd, 1H, J= 8.7, 2.6 Hz), 7.61 (dd, 1H, J = 8.7, 6.0 Hz), 7.32 (td, 1H, J = 8.7,2.6 Hz), 4.99-4.95 (m, 1H), 4.80-4.74 (m, 1H), 4.57 (s, 2H), 3.84 (dd,1H, J = 13.7, 4.0 Hz), 3.75 (dd, 1H, J = 13.7, 1.6 Hz), 3.62 (dd, 1H, J= 10.3, 5.8 Hz), 3.57 (dd, 1H, J = 10.3, 7.7 Hz), 3.25 (s, 3H), 1.17 (d,3H, J = 2.0 Hz), 1.15 (d, 3H, J = 2.0 Hz).

TABLE 1-65 structural No. formula salt ¹H-NMR 231

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (br s, 1H), 8.79 (s, 1H), 7.37 (dd, 1H, J= 8.5, 6.1 Hz), 7.10-7.01 (m, 2H), 4.99-4.95 (m, 1H), 4.80-4.74 (m, 1H),4.45 (s, 2H), 3.84 (dd, 1H, J = 13.7, 4.1 Hz), 3.75 (br d, 1H, J = 13.7Hz), 3.62 (dd, 1H, J = 10.4, 5.7 Hz), 3.57 (dd, 1H, J = 10.4, 7.6 Hz),3.25 (s, 3H), 2.29 (s, 3H), 1.17 (d, 3H, J = 2.0 Hz), 1.15 (d, 3H, J =2.0 Hz). 232

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (br s, 1H), 8.56 (s, 1H), 7.42-7.38 (m,2H), 7.20-7.16 (m, 2H), 4.66-4.64 (m, 1H), 4.47 (s, 2H), 4.45-4.40 (m,1H), 4.08-4.05 (m, 1H), 3.56 (dd, 1H, J = 11.3, 3.2 Hz), 3.50 (dd, 1H, J= 11.3, 4.2 Hz), 3.11 (s, 3H), 1.75 (d, 3H, J = 6.5 Hz), 1.33 (d, 3H, J= 6.0 Hz), 1.32 (d, 3H, J = 6.0 Hz). 233

HCl ¹H-NMR (DMSO-d₆) δ: 12.54 (br s, 1H), 8.85 (s, 1H), 7.44-7.38 (m,2H), 7.22-7.15 (m, 2H), 4.62-4.53 (m, 1H), 4.51-4.44 (m, 3H), 4.32 (dd,1H, J = 13.1, 3.4 Hz), 4.26-4.18 (m, 1H), 1.27 (d, 3H, J = 6.7 Hz), 1.26(d, 3H, J = 6.7 Hz), 1.21 (d, 3H, J = 6.5 Hz). 234

HCl ¹H-NMR (DMSO-d₆) δ: 12.85 (s, 1H), 8.43 (s, 1H), 7.69 (s, 1H),7.37-7.29 (m, 2H), 7.19-7.11 (m, 2H), 4.73 (sep, 1H, J = 6.7 Hz), 4.21(s, 2H), 4.12 (d, 1H, J = 14.1 Hz), 3.79 (d, 1H, J = 14.1 Hz), 2.93 (s,6H), 1.98 (s, 3H), 1.17 (d, 3H, J = 6.7 Hz), 1.11 (d, 3H, J = 6.7 Hz).

TABLE 1-66 structural No. formula salt ¹H-NMR 235

HCl ¹H-NMR (DMSO-d₆) δ: 12.89 (br s, 1H), 8.46 (s, 1H), 7.69 (s, 1H),7.34-7.31 (m, 2H), 7.16-7.12 (m, 2H), 4.74-4.68 (m, 1H), 4.20 (s, 2H),4.15 (d, 1H, J = 14.2 Hz), 3.78 (d, 1H, J = 14.2 Hz), 3.60-3.53 (m, 1H),3.40 (br t, 2H, J = 5.2 Hz), 3.36-3.28 (m, 1H), 3.18 (s, 3H), 2.95 (brs, 3H), 1.97 (s, 3H), 1.17 (d, 3H, J = 6.7 Hz), 1.12 (d, 3H, J = 6.7Hz). 236

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (m, 1H), 8.59 (s, 1H), 7.69 (s, 1H),7.34-7.30 (m, 2H), 7.17-7.11 (m, 2H), 4.72-4.65 (m, 1H), 4.20 (s, 2H),4.20-4.13 (m, 1H), 4.00 (d, 1H, J = 13.5 Hz), 3.86-3.80 (m, 2H),3.75-3.66 (m, 2H), 2.12-2.03 (m, 2H), 1.93 (s, 3H), 1.14 (d, 3H, J = 6.7Hz), 1.12 (d, 3H, J = 6.7 Hz). 237

HCl ¹H-NMR (DMSO-d₆) δ: 12.77 (br s, 1H), 8.55 (s, 1H), 7.69 (s, 1H),7.34-7.30 (m, 2H), 7.17-7.11 (m, 2H), 4.72-4.66 (m, 1H), 4.20 (s, 2H),4.17-3.96 (m, 4H), 3.73-3.53 (m, 3H), 3.12 (s, 3H), 2.95 (s, 3H),1.18-1.07 (m, 6H). 238

HCl ¹H-NMR (DMSO-d₆) δ: 1.280 (br s, 1H), 8.58-8.53 (m, 1H), 7.69-7.68(m, 1H), 7.34-7.30 (m, 2H), 7.16-7.12 (m, 2H), 4.72-4.66 (m, 2H), 4.20(s, 2H), 3.99-3.84 (m, 2H), 3.78-3.67 (m, 1H), 3.60-3.47 (m, 2H),3.36-3.33 (m, 2H), 3.27-3.25 (m, 1H), 3.28-3.16 (m, 3H), 1.93 (s, 3H),1.15-1.10 (m, 6H).

TABLE 1-67 structural No. formula salt ¹H-NMR 239

HCl ¹H-NMR (DMSO-d₆) δ: 12.81 (br s, 1H), 8.51 (s, 1H), 8.20 (br t, 1H,J = 5.5 Hz), 7.67 (s, 1H), 7.34-7.30 (m, 2H), 7.16-7.11 (m, 2H),4.73-4.66 (m, 1H), 4.20 (s, 2H), 4.11 (d, 1H, J = 13.7 Hz), 3.77 (d, 1H,J = 13.7 Hz), 3.13-2.99 (m, 2H), 1.92 (s, 3H), 1.14 (d, 3H, J = 6.7 Hz),1.10 (d, 3H, J = 6.7 Hz), 0.99 (t, 3H, J = 7.2 Hz). 240

HCl ¹H-NMR (DMSO-d₆) δ: 1.280 (br s, 1H), 8.80 (s, 1H), 7.29 (d, 2H, J =8.9 Hz), 6.92 (d, 2H, J = 8.9 Hz), 4.99-4.94 (m, 1H), 4.80-4.73 (m, 1H),4.39 (s, 2H), 3.84 (dd, 1H, J = 13.7, 4.0 Hz), 3.75 (d, 1H, J = 13.7Hz), 3.74 (s, 3H), 3.62 (dd, 1H, J = 10.3, 5.8 Hz), 3.57 (dd, 1H, J =10.3, 7.7 Hz), 3.25 (s, 3H), 1.17 (d, 3H, J = 2.4 Hz), 1.15 (d, 3H, J =2.4 Hz). 241

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (br s, 1H), 8.80 (s, 1H), 7.32 (dd, 2H, J= 8.5, 5.6 Hz), 7.11 (t, 2H, J = 8.5 Hz), 4.98-4.94 (m, 1H), 4.81-4.74(m, 1H), 3.84 (dd, 1H, J = 13.9, 3.8 Hz), 3.76 (d, 1H, J = 13.9 Hz),3.63 (dd, 1H, J = 10.3, 5.8 Hz), 3.57 (dd, 1H, J = 10.3, 7.5 Hz), 3.41(t, 2H, J = 7.7 Hz), 3.26 (s, 3H), 3.09 (t, 2H, J = 7.7 Hz), 1.17 (d,3H, J = 1.6 Hz), 1.15 (d, 3H, J = 1.6 Hz).

TABLE 1-68 structural No. formula salt ¹H-NMR 242

HCl ¹H-NMR (DMSO-d₆) δ: 12.81 (br s, 1H), 8.81 (s, 1H), 7.28 (dd, 2H, J= 8.5, 5.6 Hz), 7.11 (t, 2H, J = 8.5 Hz), 4.98-4.94 (m, 1H), 4.81-4.74(m ,1H), 3.85 (dd, 1H, J = 13.9, 4.0 Hz), 3.76 (dd, 1H, J = 13.9, 1.4Hz), 3.63 (dd, 1H, J = 10.3, 5.8 Hz), 3.58 (dd, 1H, J = 10.3, 7.7 Hz),3.26 (s, 3H), 3.10 (t, 2H, J = 7.7 Hz), 2.68 (t, 2H, J = 7.7 Hz),2.09-2.01 (m, 2H), 1.18 (d, 3H, J = 2.0 Hz), 1.16 (d, 3H, J = 2.0 Hz).243

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8.81 (s, 1H), 7.65-7.63 (m,1H), 7.41-7.39 (m, 2H), 5.00-4.95 (m, 1H), 4.80-4.74 (m, 1H), 4.50 (s,2H), 3.84 (dd, 1H, J = 13.7, 4.0 Hz), 3.76 (dd, 1H, J = 13.7, 1.6 Hz),3.63 (dd, 1H, J = 10.1, 5.6 Hz), 3.57 (dd, 1H, J = 10.1, 7.7 Hz), 3.25(s, 3H), 1.17 (d, 3H, J = 2.0 Hz), 1.15 (d, 3H, J = 2.0 Hz). 244

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8.81 (s, 1H), 7.73 (d, 2H, J =8.1 Hz), 7.60 (d, 2H, J = 8.1 Hz), 4.99-4.94 (m, 1H), 4.80-4.73 (m, 1H),4.61 (s, 2H), 3.84 (dd, 1H, J = 13.7, 4.0 Hz), 3.76 (dd, 1H, J = 13.7,1.6 Hz), 3.63 (dd, 1H, J = 10.1, 5.6 Hz), 3.57 (dd, 1H, J = 10.1, 7.7Hz), 3.25 (s, 3H), 1.17 (d, 3H, J = 2.0 Hz), 1.15 (d, 3H, J = 2.0 Hz).

TABLE 1-69 structural No. formula salt ¹H-NMR 245

HCl ¹H-NMR (DMSO-d₆) δ: 12.79 (br s, 1H), 8.48 (s, 1H), 8.34-8.33 (m,1H), 7.67 (s, 1H), 7.34-7.30 (m, 2H), 7.16-7.12 (m, 2H), 4.73-4.67 (m,1H), 4.20 (s, 2H), 4.06 (d, 1H, J = 13.7 Hz), 3.78 (d, 1H, J = 13.7 Hz),3.61-3.44 (m, 1H), 1.90 (s, 3H), 1.13 (d, 3H, J = 6.7 Hz), 1.09 (d, 3H,J = 6.7 Hz), 0.62 (d, 2H, J = 7.4 Hz), 0.46-0.41 (m, 2H). 246

HCl ¹H-NMR (DMSO-d₆) δ: 12.82 (br s, 1H), 8.51 (s, 1H), 8.28 (t, 1H, J =5.5 Hz), 7.67 (s, 1H), 7.33-7.30 (m, 2H), 7.16-7.11 (m, 2H), 4.73-4.66(m, 1H), 4.20 (s, 2H), 4.15 (d, 1H, J = 13.9 Hz), 3.78 (d, 1H, J = 13.9Hz), 2.98-2.84 (m, 2H), 1.93 (s, 3H), 1.14 (d, 3H, J = 7.2 Hz), 1.12 (d,3H, J = 7.2 Hz), 0.89-0.85 (m, 1H), 0.40-0.37 (m, 2H), 0.14-0.10 (m,2H). 247

HCl ¹H-NMR (DMSO-d₆) δ: 12.70 (br s, 1H), 8.51 (s, 1H), 7.71 (s, 1H),7.34-7.30 (m, 2H), 7.18-7.12 (m, 2H), 4.64-4.62 (m, 1H), 4.45-4.49 (m,1H), 4.21 (s, 2H), 4.06-4.02 (m, 1H), 3.53 (dd, 1H, J = 11.1, 3.4 Hz),3.48 (dd, 1H, J = 11.1, 4.2 Hz), 3.11 (s, 3H), 1.72 (d, 3H, J = 6.5 Hz),1.33 (d, 3H, J = 5.6 Hz), 1.31 (d, 3H, J = 5.6 Hz). 248

HCl ¹H-NMR (DMSO-d₆) δ: 12.77 (br s, 1H), 8.44 (s, 1H), 7.68 (s, 1H),7.37-7.29 (m, 2H), 7.16-7.11 (m, 2H), 4.20 (s, 2H), 4.19 (d, 1H, J =14.1 Hz), 3.93 (d, 1H, J = 14.1 Hz), 3.56-3.44 (m, 2H), 2.90 (s, 6H),1.94 (s, 3H), 1.10 (s, 3H, J = 7.2 Hz).

TABLE 1-70 structural No. formula salt ¹H-NMR 249

HCl ¹H-NMR (DMSO-d₆) δ: 12.68 (br s, 1H), 8.50 (s, 1H), 8.20 (br t, 1H,J = 5.1 Hz), 7.67 (s, 1H), 7.33-7.30 (m, 2H), 7.16-7.11 (m, 2H), 4.20(s, 2H), 4.09 (d, 1H, J = 13.7 Hz), 3.97 (d, 1H, J = 13.7 Hz), 3.64-3.55(m, 1H), 3.38-3.32 (m, 1H), 3.11-3.04 (m, 2H), 1.88 (s, 3H), 1.10 (s,3H, J = 7.2 Hz), 0.96 (s, 3H, J = 7.2 Hz). 250

HCl ¹H-NMR (DMSO-d₆) δ: 12.79 (br s, 1H), 8.81 (s, 1H), 7.23-7.16 (m,2H), 6.94-6.90 (m, 1H), 4.99-4.95 (m, 1H), 4.80-4,74 (m, 1H), 4.45 (s,2H), 3.86-3.83 (m, 1H), 3.83 (s, 3H), 3.76 (dd, 1H, J = 13.9, 1.4 Hz),3.63 (dd, 1H, J = 10.3, 5.8 Hz), 3.57 (dd, 1H, J = 10.3, 7.7 Hz), 3.25(s, 3H), 1.17 (d, 3H, J = 2.0 Hz), 1.15 (d, 3H, J = 2.0 Hz). 251

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (br s, 1H), 8.79 (s, 1H), 7.38 (dd, 1H, J= 8.5, 6.5 Hz), 7.02 (td, 1H, 8.5, 2.8 Hz), 6.81 (dd, 1H, J = 8.5, 2.8Hz), 4.98-4.94 (m, 1H), 4.78-4.64 (m, 1H), 4.60 (s, 2H), 3.83 (dd, 1H, J= 13.7, 4.0 Hz), 3.75 (dd, 1H, J = 13.7, 1.4 Hz), 3.62 (dd, 1H, J =10.3, 5.8 Hz), 3.57 (dd, 1H, J = 10.3, 7.7 Hz), 3.25 (s, 3H), 2.06-1.99(m, 1H), 1.17 (d, 3H, J = 2.0 Hz), 1.15 (d, 3H, J = 2.0 Hz), 0.90-0.84(m, 2H), 0.66-0.63 (m, 2H).

TABLE 1-71 structural No. formula salt ¹H-NMR 252

HCl ¹H-NMR (DMSO-d₆) δ: 12.40 (br s, 1H), 8.52 (s, 1H), 8.09-8.05 (m,1H), 7.65 (s, 1H), 7.34-7.29 (m, 2H), 7.16-7.10 (m, 2H), 4.67 (d, 1H, J= 13.5 Hz), 4.37 (d, 1H, J = 13.5 Hz), 4.19 (s, 2H), 3.76-3.68 (m, 1H),3.38-3.29 (m, 1H), 2.54 (d, 3H, J = 4.4 Hz), 1.65 (s, 3H), 1.51 (t, 3H,J = 7.1 Hz). 253

HCl ¹H-NMR (DMSO-d₆) δ: 12.40 (br s, 1H), 8.68 (s, 1H), 7.66 (s, 1H),7.34-7.30 (m, 2H), 7.16-7.11 (m, 2H), 4.86 (d, 1H, J = 14.1 Hz), 4.46(d, 1H, J = 14.1 Hz), 4.19 (s, 2H), 3.78-3.69 (m, 1H), 3.18-3.09 (m,1H), 2.99 (br s, 6H), 1.71 (s, 3H), 1.19 (t, 3H, J = 7.1 Hz). 254

HCl ¹H-NMR (DMSO-d₆) δ: 12.42 (br s, 1H), 8.69 (s, 1H), 7.65 (s, 1H),7.34-7.29 (m, 2H), 7.16-7.11 (m, 2H), 4.86 (d, 1H, J = 13.9 Hz), 4.46(d, 1H, J = 13.9 Hz), 4.30-4.03 (m, 1H), 4.19 (s, 2H), 3.78-3.68 (m,2H), 3.46-3.17 (m, 3H), 1.98-1.78 (m, 4H), 1.73 (s, 3H), 1.17 (t, 3H, J= 7.1 Hz). 255

HCl ¹H-NMR (DMSO-d₆) δ: 12.70 (br s, 1H), 8.61 (s, 1H), 7.70 (s, 1H),7.35-7.32 (m, 2H), 7.17-7.13 (m, 2H), 4.21 (s, 2H), 4.21-4.17 (m, 1H),4.11 (d, 1H, J = 13.7 Hz), 3.96 (d, 1H, J = 13.7 Hz), 3.89-3.82 (m, 2H),3.78-3.73 (m, 1H), 3.46 (dd, 1H, J = 13.9, 6.9 Hz), 3.25 (dd, 1H, J =13.9, 7.5 Hz), 2.14-2.06 (m, 2H), 1.94 (s, 3H), 1.09-1.03 (m, 1H),0.52-0.49 (m, 1H), 0.34-0.31 (m, 2H).

TABLE 1-72 structural No. formula salt ¹H-NMR 256

HCl ¹H-NMR (DMSO-d₆) δ: 12.77 (br s, 1H), 8.78 (s, 1H), 7.42-7.30 (m,2H), 7.20-7.16 (m, 2H), 4.72-4.70 (m, 1H), 4.60-4.53 (m, 1H), 4.47 (s,2H), 4.18-4.10 (m, 2H), 3.94 (dd, 1H, J = 11.9, 2.2 Hz), 3.46 (s, 3H),1.29 (d, 3H, J = 6.9 Hz), 1.27 (d, 3H, J = 6.9 Hz), 1.05 (d, 3H, J = 6.5Hz). 257

HCl ¹H-NMR (DMSO-d₆) δ: 12.76 (br s, 1H), 8.62 (s, 1H), 7.42-7.38 (m,2H), 7.20-7.16 (m, 2H), 4.77-4.74 (m, 1H), 4.47 (s, 2H), 4.19 (q, 1H, J= 4.0 Hz), 3.71 (dd, 1H, J = 14.1, 7.3 Hz), 3.62 (d, 2H, J = 4.4 Hz)3.23 (dd, 1H, J = 14.1, 6.9 Hz), 3.16 (s, 3H), 1.69 (d, 3H, J = 6.9 Hz),1.22-1.16 (m, 1H), 0.58-0.48 (m, 2H), 0.44-0.39 (m, 1H), 0.34-0.29 (m,1H). 258

HCl ¹H-NMR (DMSO-d₆) δ: 12.82 (br s, 1H), 8.72 (s, 1H), 7.43-7.39 (m,2H), 7.21-7.16 (m, 2H), 4.84-4.79 (m, 1H), 4.47 (s, 2H), 4.26-4.21 (m,1H), 3.89-3.76 (m, 3H), 3.33 (s, 3H), 3.33-3.26 (m, 1H), 1.24 (d, 3H, J= 6.9 Hz), 1.17 (t, 3H, J = 7.3 Hz). 259

HCl ¹H-NMR (DMSO-d₆) δ: 12.78 (br s, 1H), 8.74 (s, 1H), 7.43-7.38 (m,2H), 7.21-7.16 (m, 2H), 4.85-4.81 (m, 1H), 4.47 (s, 2H), 4.30-4.24 (m,1H), 3.93 (dd, 1H, J = 11.5, 8.5 Hz), 3.85 (dd, 1H, J = 11.5, 3.0 Hz),3.56 (dd, 1H, J = 14.1, 7.5 Hz), 3.37 (s, 3H), 3.30 (dd, 1H, J = 14.1,6.9 Hz), 1.24 (d, 3H, J = 6.9 Hz), 1.15-1.09 (m, 1H), 0.58-0.48 (m, 2H),0.41-0.30 (m, 2H).

TABLE 1-73 structural No. formula salt ¹H-NMR 260

HCl ¹H-NMR (DMSO-d₆) δ: 12.67 (br s, 1H), 8.53 (s, 1H), 7.69 (s, 1H),7.33-7.29 (m, 2H), 7.17-7.11 (m, 2H), 4.73-4.67 (m, 1H), 4.19 (s, 2H),4.10 (q, 1H, J = 4.1 Hz), 3.90-3.83 (m, 1H), 3.56 (d, 2H, J = 4.6 Hz),3.33-3.32 (m, 1H), 3.16 (s, 3H), 1.61 (d, 3H, J = 6.5 Hz), 1.20 (t, 3H,J = 7.1 Hz). 261

HCl ¹H-NMR (DMSO-d₆) δ: 12.69 (br s, 1H), 8.59 (s, 1H), 7.67 (s, 1H),7.34-7.30 (m, 2H), 7.16-7.11 (m, 2H), 4.79-4.75 (m, 1H), 4.22-4.19 (m,1H), 4.19 (s, 2H), 3.85-3.73 (m, 3H), 3.31 (s, 3H), 3.31-3.24 (m, 1H),1.22 (d, 3H, J = 6.7 Hz), 1.15 (t, 3H, J = 7.1 Hz). 262

HCl ¹H-NMR (DMSO-d₆) δ: 12.71 (br s, 1H), 8.60 (s, 1H), 7.70 (s, 1H),7.35-7.31 (m, 2H), 7.16-7.12 (m, 2H), 4.41-4.38 (m, 1H), 4.20 (s, 2H),4.10-4.02 (m, 4H), 3.98 (d, 1H, J = 13.7 Hz), 3.68-3.59 (m, 1H),3.43-3.35 (m, 1H), 3.32-3.26 (m, 1H), 3.13 (s, 3H), 1.94 (s, 3H),1.07-1.00 (m, 1H), 0.53-0.45 (m, 2H), 0.34-0.28 (m, 2H). 263

HCl ¹H-NMR (DMSO-d₆) δ: 12.69 (br s, 1H), 8.60 (s, 1H), 7.69 (s, 1H),7.34-7.31 (m, 2H), 7.14 (br t, 2H, J = 8.8 Hz), 4.39-4.36 (m, 1H), 4.20(s, 2H), 4.11-3.90 (m, 5H), 3.69-3.65 (m, 1H), 3.57-3.40 (m, 2H), 3.12(s, 3H), 1.92 (s, 3H), 1.09 (t, 3H, J = 6.6 Hz).

TABLE 1-74 structural No. formula salt ¹H-NMR 264

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (s, 1H), 8.41 (s, 1H), 7.68 (s, 1H), 7.32(dd, 2H, J = 8.2, 5.9 Hz), 7.16-7.13 (m, 2H), 4.19 (s, 2H), 4.18 (d, 1H,J = 13.9 Hz), 3.90 (d, 1H, J = 13.9 Hz), 3.05 (s, 3H), 2.88 (s, 6H),1.91 (s, 3H). 265

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (s, 1H), 8.40 (s, 1H), 7.67 (s, 1H),7.35-7.29 (m, 2H), 7.16-7.11 (m, 2H), 4.19 (s, 2H), 4.17 (d, 1H, J =13.9 Hz), 3.89 (d, 1H, J = 13.9 Hz), 3.43-3.35 (m, 1H), 3.28-3.19 (m,1H), 3.05 (s, 3H), 2.83 (s, 3H), 1.89 (s, 3H), 0.98 (t, 3H, J = 7.1 Hz).266

HCl ¹H-NMR (DMSO-d₆) δ: 12.66 (br s, 1H), 8.62 (s, 1H), 7.70 (s, 1H),7.34-7.31 (m, 2H), 7.16-7.12 (m, 2H), 4.20 (s, 2H), 4.18-4.11 (m, 1H),4.04-3.97 (m, 1H), 3.91-3.82 (m, 2H), 3.28-3.19 (m, 1H), 3.64-3.57 (m,1H), 3.03 (s, 3H), 2.09-2.03 (m, 2H), 1.90 (s, 3H). 267

HCl ¹H-NMR (DMSO-d₆) δ: 12.73 (br s, 1H), 8.50 (s, 1H), 8.18 (br t, 1H,J = 5.6 Hz), 7.67 (s, 1H), 7.34-7.29 (m, 2H), 7.17-7.11 (m, 2H), 4.20(s, 2H), 3.99 (d, 1H, J = 13,7 Hz), 3.93 (d, 1H, J = 13.7 Hz), 3.08-3.01(m, 2H), 2.87-2.84 (m, 1H), 1.87 (s, 3H), 0.96 (t, 3H, J = 7.2 Hz),0.94-0.89 (m, 1H), 0.81-0.69 (m, 2H), 0.62-0.56 (m, 1H).

TABLE 1-75 No. structural formula salt ¹H-NMR 268

HCl ¹H-NMR (DMSO-d₆) δ: 12.70 (br s, 1H), 8.61 (s, 1H), 7.69 (s, 1H),7.34-7.30 (m, 2H), 7.16-7.11 (m, 2H), 4.20 (s, 2H), 4.07-4.01 (m, 1H),3.92 (d, 1H, J = 13.2 Hz), 3.87-3.82 (m, 2H), 3.80 (d, 1H, J = 13.2 Hz),3.50-3.42 (m, 1H), 2.89-2.84 (m, 1H), 2.08-2.00 (m, 2H), 1.89 (s, 3H),0.91-0.85 (m, 1H), 0.82-0.73 (m, 2H), 0.67-0.61 (m, 1H). 269

HCl ¹H-NMR (DMSO-d₆) δ: 13.18 (br s, 1H), 8.67 (s, 1H), 7.42-7.38 (m,2H), 7.20-7.14 (m, 2H), 4.46 (s, 2H), 3.83 (d, 1H, J = 13.7 Hz), 3.74(d, 1H, J = 13.7 Hz), 3.64 (d, 1H, J = 11.8 Hz), 3.62 (d, 1H, J = 11.8Hz), 3.60-3.44 (m, 3H), 1.59 (s, 3H), 1.15 (t, 3H, J = 7.2 Hz). 270

HCl ¹H-NMR (DMSO-d₆) δ: 12.69 (br s, 1H), 8.75 (s, 1H), 7.41-7.38 (m,2H), 7.20-7.15 (m, 2H), 4.53 (d, 1H, J = 13.7 Hz), 4.46 (s, 2H), 4.30(d, 1H, J = 13.7 Hz), 3.68-3.59 (m, 1H), 3.51 (d, 1H, J = 10.4 Hz),3.48-3.43 (m, 2H), 3.20 (s, 3H), 1.35 (s, 3H), 1.19 (t, 3H, J = 7.1 Hz).271

HCl ¹H-NMR (DMSO-d₆) δ: 12.69 (br s, 1H), 8.61 (s, 1H), 7.69 (s, 1H),7.34-7.31 (m, 2H), 7.16-7.12 (m, 2H), 4.20 (s, 2H), 4.17-4.15 (m, 1H),4.02 (d, 1H, J = 13.5 Hz), 4.00-3.87 (m, 2H), 3.89 (d, 1H, J = 13.5 Hz),3.65-3.63 (m, 1H), 3.54-3.44 (m, 2H), 2.10-2.06 (m, 2H), 1.91 (s, 3H),1.10 (t, 3H, J = 7.1 Hz).

TABLE 1-76 No. structural formula salt ¹H-NMR 272

HCl ¹H-NMR (DMSO-d₆) δ: 12.65 (br s, 1H), 8.66 (s, 1H), 7.64 (s, 1H),7.47-7.41 (m, 1H), 7.24 (dt, 1H, J = 14.0, 5.0 Hz), 7.06 (td, 1H, J =8.5, 2.3 Hz), 5.10-5.03 (m, 1H), 4.80-4.73 (m, 1H), 4.20 (s, 2H),4.18-4.04 (m, 2H), 3.98-3.85 (m, 1H), 3.87-3.71 (m, 3H), 3.61-3.53 (m,1H), 3.15 (s, 1.5H), 3.08 (s, 1.5H), 2.66-2.58 (m, 2H), 1.15-1.11 (m,6H). 273

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8.59 (s, 1H), 7.70 (s, 1H),7.35-7.32 (m, 2H), 7.17-7.13 (m, 2H), 4.21 (s, 2H), 4.21-4.17 (m, 1H),4.14 (d, 1H, J = 13.7 Hz), 3.93-3.76 (m, 5H), 2.16-2.08 (m, 2H), 1.97(s, 3H), 1.24 (d, 3H, J = 6.8 Hz), 1.13-1.10 (m, 1H), 0.64-0.58 (m, 1H),0.43-0.38 (m, 2H), 0.20-0.15 (m, 1H). 274

HCl ¹H-NMR (DMSO-d₆) δ: 12.81 (br s, 1H), 8.58 (s, 1H), 7.70 (s, 1H),7.35-7.32 (m, 2H), 7.17-7.13 (m, 2H), 4.21 (s, 2H), 4.21-4.14 (m, 3H),4.06-4.00 (m, 1H), 3.87-3.64 (m, 4H), 3.15 (s, 3H), 1.98 (s, 3H), 1.24(d, 3H, J = 6.6 Hz), 1.13-1.09 (m, 1H), 0.61-0.57 (m, 1H), 0.49-0.36 (m,2H), 0.15-0.07 (m, 1H).

TABLE 1-77 No. structural formula salt ¹H-NMR 275

HCl ¹H-NMR (DMSO-d₆) δ: 12.84 (br s, 1H), 8.48 (s, 1H), 7.69 (s, 1H),7.35-7.32 (m, 2H), 7.17-7.13 (m, 2H), 4.31 (d, 1H, J = 14.3 Hz), 4.21(s, 2H), 3.93 (d, 1H, J = 14.3 Hz), 3.83-3.75 (m, 1H), 2.98 (br s, 6H),2.05 (s, 3H), 1.25 (d, 3H, J = 6.8 Hz), 1.10-1.03 (m, 1H), 0.64-0.58 (m,1H), 0.42-0.33 (m, 2H), 0.12-0.08 (m, 1H). 276

HCl ¹H-NMR (DMSO-d₆) δ: 12.86 (br s, 1H), 8.52 (s, 1H), 8.21 (t, 1H, J =5.4 Hz), 7.69 (s, 1H), 7.36-7.31 (m, 2H), 7.18-7.13 (m, 2H), 4.29 (d,1H, J = 13.7 Hz), 4.21 (s, 2H), 3.87 (d, 1H, J = 13.7 Hz), 3.81-3.73 (m,1H), 3.20-3.14 (m, 1H), 3.02-2.96 (m, 1H), 1.94 (s, 3H), 1.24 (d, 3H, J= 6.8 Hz), 1.13-1.07 (m, 1H), 1.01 (t, 3H, J = 7.2 Hz), 0.62-0.57 (m,1H), 0.37-0.31 (m, 2H), 0.18-0.12 (m, 1H). 277

HCl ¹H-NMR (DMSO-d₆) δ: 12.82 (br s, 1H), 8.80 (s, 1H), 7.38-7.32 (m,2H), 4.99-4.97 (m, 1H), 4.80-4.74 (m, 1H), 4.46 (s, 2H), 3.84 (dd, 1H, J= 13.5, 4.2 Hz), 3.83 (s, 3H), 3.75 (dd, 1H, J = 13.5, 1.2 Hz), 3.63(dd, 1H, J = 10.3, 5.8 Hz), 3.57 (dd, 1H, J = 10.3, 7.7 Hz), 3.25 (s,3H), 1.17 (d, 3H, J = 2.0 Hz), 1.15 (d, 3H, J = 2.0 Hz).

TABLE 1-78 No. structural formula salt ¹H-NMR 278

HCl ¹H-NMR (DMSO-d₆) δ: 12.45 (br s, 1H), 8.98 (s, 1H), 7.43-7.38 (m,2H), 7.21-7.16 (m, 2H), 4.71-4.67 (m, 1H), 4.56-4.49 (m, 1H), 4.47 (s,2H), 4.30-4.25 (m, 1H), 3.93-3.90 (m, 1H), 1.65-1.61 (m, 1H), 1.46-1.38(m, 1H), 1.29 (d, 3H, J = 2.4 Hz), 1.27 (d, 3H, J = 2.0 Hz), 0.92 (t,3H, J = 7.5 Hz). 279

HCl ¹H-NMR (DMSO-d₆) δ: 12.60 (br s, 1H), 8.84 (s, 1H), 7.43-7.38 (m,2H), 7.20-7.15 (m, 2H), 4.50-4.46 (m, 1H), 4.46 (s, 2H), 4.41 (dd, 1H, J= 13.1, 3.6 Hz), 4.20-4.17 (m, 1H), 3.57 (dd, 1H, J = 14.0, 7.1 Hz),3.22 (dd, 1H, J = 14.0, 7.0 Hz), 1.24 (d, 3H, J = 6.5 Hz), 1.14-1.10 (m,1H), 0.56-0.47 (m, 2H), 0.39-0.36 (m, 1H), 0.33-0.29 (m, 1H). 280

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (br s, 1H), 8.61 (s, 1H), 7.70 (s, 1H),7.35-7.32 (m, 2H), 7.18-7.13 (m, 2H), 4.21 (s, 2H), 4.21-4.13 (m, 2H),3.86-3.73 (m, 5H), 2.14-2.06 (m, 2H), 1.96 (s, 3H), 1.20 (d, 3H, J = 6.6Hz), 1.15-1.07 (m, 1H), 0.64-0.58 (m, 1H), 0.45-0.38 (m, 2H), 0.23-0.20(m, 1H). 281

HCl ¹H-NMR (DMSO-d₆) δ: 12.74 (br s, 1H), 8.60 (s, 1H), 7.70 (s, 1H),7.36-7.32 (m, 2H), 7.17-7.13 (m, 2H), 4.21 (s, 2H), 4.15-4.04 (m, 4H),3.89-3.78 (m, 2H), 3.68-3.58 (m, 2H), 3.15 (s, 1.5H), 3.14 (s, 1.5H),1.98 (s, 3H), 1.19-1.11 (m, 4H), 0.61-0.57 (m, 1H), 0.49-0.38 (m, 2H),0.22-0.19 (m, 1H).

TABLE 1-79 No. structural formula salt ¹H-NMR 282

HCl ¹H-NMR (DMSO-d₆) δ: 12.84 (br s, 1H), 8.42 (s, 1H), 7.69 (s, 1H),7.35-7.32 (m, 2H), 7.18-7.12 (m, 2H), 4.24 (d, 1H, J = 14.3 Hz), 4.21(s, 2H), 3.93 (d, 1H, J = 14.3 Hz), 3.89-3.81 (m, 1H), 2.94 (br s, 6H),1.99 (s, 3H), 1.19 (d, 3H, J = 6.6 Hz), 1.15-1.09 (m, 1H), 0.63-0.58 (m,1H), 0.48-0.39 (m, 2H), 0.26-0.22 (m, 1H). 283

HCl ¹H-NMR (DMSO-d₆) δ: 12.77 (br s, 1H), 8.53 (s, 1H), 8.25 (t, 1H, J =5.4 Hz), 7.69 (s, 1H), 7.35-7.32 (m, 2H), 7.17-7.13 (m, 2H), 4.29 (d,1H, J = 13.9 Hz), 4.21 (s, 2H), 3.92 (d, 1H, J = 13.9 Hz), 3.89-3.83 (m,1H), 3.16-3.02 (m, 2H), 1.95 (s, 3H), 1.18 (d, 3H, J = 6.8 Hz),1.03-1.01 (m, 1H), 1.01 (t, 3H, J = 7.2 Hz), 0.62-0.58 (m, 1H),0.47-0.39 (m, 2H), 0.24-0.19 (m, 1H). 284

HCl ¹H-NMR (DMSO-d₆) δ: 12.66 (br s, 1H), 8.82 (s, 1H), 7.43-7.39 (m,2H), 7.21-7.16 (m, 2H), 4.83 (br t, 1H, J = 6.6 Hz), 4.48 (s, 2H), 4.04(q, 1H, J = 6.2 Hz), 3.95-3.86 (m, 1H), 3.64 (dd, 1H, J = 10.4, 5.3 Hz),3.53 (dd, 1H, J = 10.4, 7.9 Hz), 3.24 (s, 3H), 3.16-3.07 (m, 1H), 1.26(d, 3H, J = 6.6 Hz), 1.16 (t, 3H, J = 7.1 Hz).

TABLE 1-80 No. structural formula salt ¹H-NMR 285

HCl ¹H-NMR (DMSO-d₆) δ: 12.67 (br s, 1H), 8.82 (s, 1H), 7.43-7.39 (m,2H), 7.22-7.15 (m, 2H), 4.82 (br t, 1H, J = 6.0 Hz), 4.65-4.58 (m, 1H),4.48 (s, 2H), 4.16 (q, 1H, J = 6.5 Hz), 3.60 (dd, 1H, J = 10.3, 5.4 Hz),3.49 (dd, 1H, J = 10.3, 7.9 Hz), 3.24 (s, 3H), 1.21 (d, 3H, J = 2.0 Hz),1.26 (d, 3H, J = 2.0 Hz), 1.21 (t, 3H, J = 6.8 Hz). 286

HCl ¹H-NMR (DMSO-d₆) δ: 12.53 (br s, 1H), 9.01 (s, 1H), 7.43-7.38 (m,2H), 7.21-7.15 (m, 2H), 4.75 (d, 1H, J = 13.8 Hz), 4.47 (s, 2H), 4.34(dd, 1H, J = 13.8, 4.3 Hz), 4.01 (td, 1H, J = 13.8, 6.9 Hz), 3.74 (br t,1H, J = 5.0 Hz), 3.74 (td, 1H, J = 13.8, 6.9 Hz), 1.92 (td, 1H, J =13.8, 6.9 Hz), 1.20 (t, 3H, J = 6.9 Hz), 0.99 (d, 3H, J = 6.9 Hz), 0.79(d, 3H, J = 6.9 Hz). 287

HCl ¹H-NMR (DMSO-d₆) δ: 12.53 (br s, 1H), 9.01 (s, 1H), 7.43-7.38 (m,2H), 7.21-7.15 (m, 2H), 4.75 (d, 1H, J = 13.8 Hz), 4.47 (s, 2H), 4.34(dd, 1H, J = 13.8, 4.3 Hz), 4.01 (td, 1H, J = 13.8, 6.9 Hz), 3.74 (br t,1H, J = 5.0 Hz), 3.74 (td, 1H, J = 13.8, 6.9 Hz), 1.92 (td, 1H, J =13.8, 6.9 Hz), 1.20 (t, 3H, J = 6.9 Hz), 0.99 (d, 3H, J = 6.9 Hz), 0.79(d, 3H, J = 6.9 Hz).

TABLE 1-81 No. structural formula salt ¹H-NMR 288

HCl ¹H-NMR (DMSO-d₆) δ: 12.67 (br s, 1H), 8.82 (s, 1H), 7.43-7.39 (m,2H), 7.22-7.15 (m, 2H), 4.82 (br t, 1H, J = 6.0 Hz), 4.65-4.58 (m, 1H),4.48 (s, 2H), 4.16 (q, 1H, J = 6.5 Hz), 3.60 (dd, 1H, J = 10.3, 5.4 Hz),3.49 (dd, 1H, J = 10.3, 7.9 Hz), 3.24 (s, 3H), 1.27 (d, 3H, J = 2.0 Hz),1.26 (d, 3H, J = 2.0 Hz), 1.21 (t, 3H, J = 6.8 Hz). 289

HCl ¹H-NMR (DMSO-d₆) δ: 12.66 (br s, 1H), 8.82 (s, 1H), 7.43-7.39 (m,2H), 7.21-7.16 (m, 2H), 4.83 (br t, 1H, J = 6.6 Hz), 4.48 (s, 2H), 4.04(q, 1H, J = 6.2 Hz), 3.95-3.86 (m, 1H), 3.64 (dd, 1H, J =10.4, 5.3 Hz),3.53 (dd, 1H, J = 10.4, 7.9 Hz), 3.24 (s, 3H), 3.16-3.07 (m, 1H), 1.26(d, 3H, J = 6.6 Hz), 1.16 (t, 3H, J = 7.1 Hz). 290

HCl ¹H-NMR (DMSO-d₆) δ: 12.86 (br s, 1H), 8.56 (s, 1H), 7.70 (s, 1H),7.37-7.31 (m, 2H), 7.19-7.12 (m, 2H), 4.73-4.66 (m, 1H), 4.21 (s, 2H),4.19-4.07 (m, 2H), 3.86-3.70 (m, 6H), 2.03 (s, 3H), 1.17 (d, 3H, J = 6.5Hz), 1.10 (d, 3H, J = 6.5 Hz). 291

HCl ¹H-NMR (DMSO-d₆) δ: 12.53 (br s, 1H), 8.96 (s, 1H), 7.43-7.38 (m,2H), 7.21-7.16 (m, 2H), 4.65 (d, 1H, J = 13.5 Hz), 4.47 (s, 2H), 4.35(dd, 1H, J = 13.5, 3.8 Hz), 3.92-3.84 (m, 2H), 3.24-3.16 (m, 1H),1.72-1.66 (m, 1H), 1.51-1.41 (m, 1H), 1.20 (t, 3H, J = 7.3 Hz), 0.92 (t,3H, J = 7.5 Hz).

TABLE 1-82 No. structural formula salt ¹H-NMR 292

HCl ¹H-NMR (DMSO-d₆) δ: 12.40 (br s, 1H), 8.52 (s, 1H), 8.09-8.05 (m,1H), 7.65 (s, 1H), 7.34-7.29 (m, 2H), 7.16-7.10 (m, 2H), 4.67 (d, 1H, J= 13.5 Hz), 4.37 (d, 1H, J = 13.5 Hz), 4.19 (s, 2H), 3.76-3.68 (m, 1H),3.38-3.29 (m, 1H), 2.54 (d, 3H, J = 4.4 Hz), 1.65 (s, 3H), 1.51 (t, 3H,J = 7.1 Hz). 293

HCl ¹H-NMR (DMSO-d₆) δ: 12.40 (br s, 1H), 8.68 (s, 1H), 7.66 (s, 1H),7.34-7.30 (m, 2H), 7.16-7.11 (m, 2H), 4.86 (d, 1H, J = 14.1 Hz), 4.46(d, 1H, J = 14.1 Hz), 4.19 (s, 2H), 3.78-3.69 (m, 1H), 3.18-3.09 (m,1H), 2.99 (br s, 6H), 1.71 (s, 3H), 1.19 (t, 3H, J = 7.1 Hz). 294

HCl ¹H-NMR (DMSO-d₆) δ: 12.42 (br s, 1H), 8.69 (s, 1H), 7.65 (s, 1H),7.34-7.29 (m, 2H), 7.16-7.11 (m, 2H), 4.86 (d, 1H, J = 13.9 Hz), 4.46(d, 1H, J = 13.9 Hz), 4.30-4.03 (m, 1H), 4.19 (s, 2H), 3.78-3.68 (m,2H), 3.46-3.17 (m, 3H), 1.98-1.78 (m, 4H), 1.73 (s, 3H), 1.17 (t, 3H, J= 7.1 Hz). 295

HCl ¹H-NMR (DMSO-d₆) δ: 12.46 (br s, 1H), 8.84 (s, 1H), 7.43-7.39 (m,2H), 7.20-7.15 (m, 2H), 4.68 (d, 1H, J = 13.5 Hz), 4.46 (s, 2H), 4.36(dd, 1H, J = 13.5, 3.7 Hz), 4.08-4.00 (m, 2H), 3.49 (dd, 1H, J = 10.2,3.9 Hz), 3.41 (dd, 1H, J = 10.2, 7.0 Hz), 3.17 (s, 3H), 1.77-1.59 (m,4H), 0.90 (t, 3H, J = 7.3 Hz), 0.85 (t, 3H, J = 7.3 Hz).

TABLE 1-83 No. structural formula salt ¹H-NMR 296

HCl ¹H-NMR (DMSO-d₆) δ: 13.19 (br s, 1H), 8.71 (s, 1H), 7.43-7.38 (m,2H), 7.21-7.16 (m, 2H), 4.47 (s, 2H), 3.86-3.76 (m, 3H), 3.70 (d, 1H, J= 10.4 Hz), 3.63-3.45 (m, 4H), 3.35-3.33 (m, 2H), 3.11 (s, 3H), 1.64 (s,3H), 1.17 (t, 3H, J = 7.2 Hz). 297

HCl ¹H-NMR (DMSO-d₆) δ: 13.21 (br s, 1H), 8.71 (s, 1H), 7.42-7.38 (m,2H), 7.21-7.16 (m, 2H), 4.47 (s, 2H), 3.80-3.63 (m, 4H), 3.51-3.44 (m,2H), 3.35-3.33 (m, 2H), 3.12 (s, 3H), 2.95-2.90 (m, 1H), 1.62 (s, 3H),0.93-0.76 (m, 4H). 298

HCl ¹H-NMR (DMSO-d₆) δ: 12.51 (br s, 1H), 8.93 (s, 1H), 7.42-7.38 (m,2H), 7.21-7.16 (m, 2H), 4.91 (q, 1H, J = 6.8 Hz), 4.48 (s, 2H),4.04-3.95 (m, 2H), 3.52 (dd, 1H, J = 10.3, 5.2 Hz), 3.46 (dd, 1H, J =10.3, 6.5 Hz), 3.22 (s, 3H), 3.20-3.13 (m, 1H), 1.42 (d, 3H, J = 6.6Hz), 1.19 (t, 3H, J = 7.1 Hz). 299

HCl ¹H-NMR (DMSO-d₆) δ: 12.48 (br s, 1H), 8.95 (s, 1H), 7.42-7.38 (m,2H), 7.21-7.16 (m, 2H), 4.95 (q, 1H, J = 6.5 Hz), 4.58-4.51 (m, 1H),4.48 (s, 2H), 4.07-4.04 (m, 1H), 3.50 (dd, 1H, J = 10.5, 4.1 Hz), 3.36(dd, 1H, J = 10.5, 7.9 Hz), 3.22 (s, 3H), 1.39 (d, 3H, J = 6.8 Hz), 1.29(d, 3H, J = 5.0 Hz), 1.27 (d, 3H, J = 5.0 Hz).

TABLE 1-84 No. structural formula salt ¹H-NMR 300

HCl ¹H-NMR (DMSO-d₆) δ: 12.50 (br s, 1H), 8.82 (s, 1H), 7.39 (dd, 1H, J= 15.3, 8.7 Hz), 7.22-7.16 (m, 1H), 7.02 (td, 1H, J = 8.7, 2.4 Hz), 4.63(d, 1H, J = 13.3 Hz), 4.42 (dd, 1H, J = 13.3, 4.3 Hz), 4.17-4.13 (m,1H), 3.87 (td, 1H, J = 14.0. 7.1 Hz), 3.56-3.49 (m, 2H), 3.40 (t, 2H, J= 7.5 Hz), 3.32-3.25 (m, 1H), 3.22 (s, 3H), 3.09 (t, 2H, J = 7.5 Hz),1.21 (t, 3H, J = 7.1 Hz). 301

HCl ¹H-NMR (DMSO-d₆) δ: 12.61 (br s, 1H), 8.78 (s, 1H), 7.42-7.39 (m,2H), 7.20-7.16 (m, 2H), 4.51 (s, 2H), 4.47 (s, 2H), 3.65-3.53 (m, 6H),3.26 (s, 6H), 1.19 (t, 3H, J = 7.1 Hz). 302

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (br s, 1H), 8.80 (s, 1H), 7.43-7.38 (m,2H), 7.21-7.15 (m, 2H), 4.99-4.95 (m, 1H), 4.46 (s, 2H), 3.99-3.84 (m,3H), 3.63 (dd, 1H, J = 10.3, 5.7 Hz), 3.57 (dd, 1H, J = 10.3, 7.7 Hz),3.24 (s, 3H), 1.22 (d, 3H, J = 7.0 Hz), 1.08-1.00 (m, 1H), 0.61-0.55 (m,1H), 0.47-0.36 (m, 2H), 0.23-0.18 (m, 1H). 303

HCl ¹H-NMR (DMSO-d₆) δ: 12.50 (br s, 1H), 8.97 (s, 1H), 7.43-7.39 (m,2H), 7.21-7.16 (m, 2H), 4.69 (d, 1H, J = 13.3 Hz), 4.48 (s, 2H), 4.38(dd, 1H, J = 13.3, 3.4 Hz), 3.95-3.93 (m, 1H), 3.69 (dd, 1H, J = 13.9,7.1 Hz), 3.16 (dd, 1H, J = 13.9, 7.2 Hz), 1.79-1.72 (m, 1H), 1.48-1.40(m, 1H), 1.19-1.12 (m, 1H), 0.93 (t, 3H, J = 7.4 Hz), 0.55-0.48 (m, 2H),0.42-0.37 (m, 1H), 0.34-0.30 (m, 1H).

TABLE 1-85 No. structural formula salt ¹H-NMR 304

HCl ¹H-NMR (DMSO-d₆) δ: 12.48 (br s, 1H), 8.95 (s, 1H), 7.42-7.38 (m,2H), 7.21-7.16 (m, 2H), 4.95 (q, 1H, J = 6.5 Hz), 4.58-4.51 (m, 1H),4.48 (s, 2H), 4.07-4.04 (m, 1H), 3.50 (dd, 1H, J = 10.5, 4.1 Hz), 3.36(dd, 1H, J = 10.5, 7.9 Hz), 3.22 (s, 3H), 1.39 (d, 3H, J = 6.8 Hz), 1.29(d, 3H, J = 5.0 Hz), 1.27 (d, 3H, J = 5.0 Hz). 305

HCl ¹H-NMR (DMSO-d₆) δ: 12.51 (br s, 1H), 8.93 (s, 1H), 7.42-7.38 (m,2H), 7.21-7.16 (m, 2H), 4.91 (q, 1H, J = 6.8 Hz), 4.48 (s, 2H),4.04-3.95 (m, 2H), 3.52 (dd, 1H, J = 10.3, 5.2 Hz), 3.46 (dd, 1H, J =10.3, 6.5 Hz), 3.22 (s, 3H), 3.20-3.13 (m, 1H), 1.42 (d, 3H, J = 6.6Hz), 1.19 (t, 3H, J = 7.1 Hz). 306

HCl ¹H-NMR (DMSO-d₆) δ: 12.70 (br s, 1H), 8.86 (s, 1H), 7.44-7.38 (m,2H), 7.22-7.15 (m, 2H), 4.80 (d, 1H, J = 14.0 Hz), 4.49 (d, 1H, J = 14.0Hz), 4.47 (s, 2H), 4.11-3.06 (m, 4H), 3.60 (sep, 1H, J = 6.6 Hz),2.06-1.63 (m, 4H), 1.73 (s, 3H), 1.46 (d, 3H, J = 6.6 Hz), 1.43 (d, 3H,J = 6.6 Hz). 307

HCl ¹H-NMR (DMSO-d₆) δ: 12.65 (br s, 1H), 8.74 (s, 1H), 8.31 (t, 1H, J =5.5 Hz), 7.44-7.38 (m, 2H), 7.22-7.15 (m, 2H), 4.58 (d, 1H, J = 13.5Hz), 4.48 (d, 1H, J = 13.5 Hz), 4.47 (s, 2H), 3.53 (sep, 1H, J = 6.6Hz), 3.20-3.09 (m, 2H), 1.58 (s, 3H), 1.48 (d, 3H, J = 6.6 Hz), 1.41 (d,3H, J = 6.6 Hz), 1.01 (t, 3H, J = 7.2 Hz).

TABLE 1-86 No. structural formula salt ¹H-NMR 308

HCl ¹H-NMR (DMSO-d₆) δ: 12.68 (br s, 1H), 8.74 (s, 1H), 8.11 (d, 1H, J =7.7 Hz), 7.45-7.38 (m, 2H), 7.22-7.15 (m, 2H), 4.61 (d, 1H, J = 14.0Hz), 4.49 (d, 1H, J = 14.0 Hz), 4.47 (s, 2H), 3.91 (sep, 1H, J = 6.6Hz), 3.48 (sep, 1H, J = 6.6 Hz), 1.55 (s, 3H), 1.51 (d, 3H, J = 6.6 Hz),1.41 (d, 3H, J = 6.6 Hz), 1.09 (d, 3H, J = 6.6 Hz), 1.06 (d, 3H, J = 6.6Hz). 309

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (br s, 1H), 8.75 (s, 1H), 7.77 (s, 1H),7.44-7.37 (m, 2H), 7.22-7.15 (m, 2H), 4.67 (d, 1H, J = 13.5 Hz), 4.49(d, 1H, J = 13.5 Hz), 4.47 (s, 2H), 3.40 (sep, 1H, J = 6.7 Hz), 1.54 (d,3H, J = 6.7 Hz), 1.50 (s, 3H), 1.41 (d, 3H, J = 6.7 Hz), 1.29 (s, 9H).310

HCl ¹H-NMR (DMSO-d₆) δ: 12.66 (br s, 1H), 8.85 (s, 1H), 7.44-7.38 (m,2H), 7.22-7.15 (m, 2H), 4.68-3.76 (m, 4H), 4.64 (d, 1H, J = 13.9 Hz),4.47 (s, 2H), 4.46 (d, 1H, J = 13.9 Hz), 3.69 (sep, 1H, J = 6.7 Hz),2.28-2.15 (m, 2H), 1.66 (s, 3H), 1.44 (d, 3H, J = 6.7 Hz), 1.43 (d, 3H,J = 6.7 Hz). 311

HCl ¹H-NMR (DMSO-d₆) δ: 12.67 (br s, 1H), 8.81 (s, 1H), 7.45-7.38 (m,2H), 7.22-7.15 (m, 2H), 4.71 (d, 1H, J = 14.0 Hz), 4.58 (d, 1H, J = 14.0Hz), 4.47 (s, 2H), 3.75-3.40 (m, 9H), 1.66 (s, 3H), 1.53 (d, 3H, J = 6.6Hz), 1.42 (d, 3H, J = 6.6 Hz).

TABLE 1-87 No. structural formula salt ¹H-NMR 312

HCl ¹H-NMR (DMSO-d₆) δ: 13.99 (br s, 1H), 12.50 (br s, 1H), 8.83 (s,1H), 7.45-7.37 (m, 2H), 7.23-7.13 (m, 2H), 4.78 (d, 1H, J = 14.0 Hz),4.49 (d, 1H, J = 14.0 Hz), 4.47 (s, 2H), 3.85 (sep, 1H, J = 6.8 Hz),1.66 (s, 3H), 1.49 (d, 3H, J = 6.8 Hz), 1.45 (d, 3H, J = 6.8 Hz). 313

HCl ¹H-NMR (DMSO-d₆) δ: 12.88 (br s, 1H), 8.55 (s, 1H), 7.45-7.38 (m,2H), 7.22-7.15 (m, 2H), 4.48 (s, 2H), 4.21 (d, 1H, J = 14.0 Hz), 3.96(d, 1H, J = 14.0 Hz), 3.07 (s, 3H), 2.91 (s, 6H), 1.98 (s, 3H). 314

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (br s, 1H), 8.42 (s, 1H), 7.69 (s, 1H),7.36-7.30 (m, 2H), 7.18-7.11 (m, 2H), 4.21 (s, 2H), 4.20 (d, 1H, J =13.9 Hz), 3.91 (d, 1H, J = 13.9 Hz), 3.07 (s, 3H), 2.89 (s, 6H), 1.92(s, 3H). 315

HCl ¹H-NMR (DMSO-d₆) δ: 12.70 (br s, 1H), 8.84 (s, 1H), 7.44-7.38 (m,2H), 7.22-7.16 (m, 2H), 4.80 (d, 1H, J = 13.9 Hz), 4.53 (d, 1H, J = 13.9Hz), 4.47 (s, 2H), 3.45 (sep, 1H, J = 6.6 Hz), 3.08 (s, 6H), 1.05 (s,3H), 1.49 (d, 3H, J = 6.6 Hz), 1.42 (d, 3H, J = 6.6 Hz).

TABLE 1-88 No. structural formula salt ¹H-NMR 316

HCl ¹H-NMR (DMSO-d₆) δ: 12.79 (br s, 1H), 8.80 (s, 1H), 7.45-7.39 (m,2H), 7.23-7.15 (m, 2H), 5.06-4.97 (m, 1H), 4.48 (s, 2H), 3.94-3.91 (m,2H), 3.90-3.80 (m, 1H), 3.72-3.58 (m, 2H), 3.26 (s, 3H), 1.23 (d, 3H, J= 6.8 Hz), 1.18-1.07 (m, 1H), 0.66-0.57 (m, 1H), 0.50-0.37 (m, 2H),0.31-0.20 (m, 1H). 317

HCl ¹H-NMR (DMSO-d₆) δ: 12.48 (br s, 1H), 8.84 (s, 1H), 7.44-7.36 (m,1H), 7.23-7.15 (m, 1H), 7.06-6.98 (m, 1H), 4.66 (dd, 1H, J = 13.6, 1.4Hz), 4.48 (sep, 1H, J = 6.8 Hz), 4.35 (dd, 1H, J = 13.6, 3.6 Hz),4.24-4.17 (m, 1H), 3.50 (dd, 1H, J = 10.4, 4.2 Hz), 3.44-3.37 (m, 3H),3.22 (s, 3H), 3.09 (t, 2H, J = 7.5 Hz), 1.30 (d, 3H, J = 6.8 Hz), 1.29(d, 3H, J = 6.8 Hz). 318

HCl ¹H-NMR (DMSO-d₆) δ: 12.71 (br s, 1H), 8.76 (s, 1H), 7.44-7.37 (m,2H), 7.22-7.15 (m, 2H), 4.55 (d, 1H, J = 13.5 Hz), 4.47 (s, 2H), 4.31(d, 1H, J = 13.5 Hz), 3.71-3.59 (m, 1H), 3.56-3.42 (m, 3H), 3.21 (s,3H), 1.37 (s, 3H), 1.20 (t, 3H, J = 7.1 Hz). 319

HCl ¹H-NMR (DMSO-d₆) δ: 12.63 (br s, 1H), 8.77 (s, 1H), 7.58-7.48 (m,1H), 7.33-7.25 (m, 1H), 7.16-7.08 (m, 1H), 4.52 (s, 2H), 4.49 (s, 2H),3.63 (d, 2H, J = 10.6 Hz), 3.58 (q, 2H, J = 7.1 Hz), 3.54 (d, 2H, J =10.6 Hz), 3.26 (s, 6H), 1.19 (t, 3H, J = 7.1 Hz).

TABLE 1-89 No. structural formula salt ¹H-NMR 320

HCl ¹H-NMR (DMSO-d₆) δ: 12.74 (br s, 1H), 8.74 (s, 1H), 7.44-7.37 (m,2H), 7.22-7.14 (m, 2H), 4.50 (s, 2H), 4.47 (s, 2H), 3.94 (sep, 1H, J =6.6 Hz), 3.66 (d, 2H, J = 10.6 Hz), 3.51 (d, 2H, J = 10.6 Hz), 3.27 (s,6H), 1.45 (d, 6H, J = 6.6 Hz). 321

HCl ¹H-NMR (DMSO-d₆) δ: 12.71 (br s, 1H), 8.83 (s, 1H), 7.58-7.50 (m,1H), 7.33-7.26 (m, 1H), 7.15-7.08 (m, 1H), 4.80 (d, 1H, J = 14.0 Hz),4.54 (d, 1H, J = 14.0 Hz), 4.49 (s, 2H), 3.45 (sep, 1H, 6.7 Hz), 3.07(s, 6H), 1.65 (s, 3H), 1.49 (d, 3H, J = 6.7 Hz), 1.42 (d, 3H, J = 6.7Hz). 322

HCl ¹H-NMR (DMSO-d₆) δ: 13.25 (br s, 1H), 8.71 (s, 1H), 7.44-7.38 (m,2H), 7.22-7.15 (m, 2H), 4.79 (sep, 1H, J = 6.8 Hz), 4.47 (s, 2H),3.80-3.73 (m, 2H), 3.71-3.64 (m, 2H), 3.55-3.43 (m, 2H), 3.37-3.31 (m,2H), 3.11 (s, 3H), 1.65 (s, 3H), 1.18 (d, 3H, J = 6.8 Hz), 1.18 (d, 3H,J = 6.8 Hz). 323

HCl ¹H-NMR (DMSO-d₆) δ: 12.69 (br s, 1H), 8.73 (s, 1H), 7.44-7.38 (m,2H), 7.23-7.15 (m, 2H), 4.55 (d, 1H, J = 13.5 Hz), 4.47 (s, 2H), 4.31(d, 1H, J = 13.5 Hz), 3.71-3.46 (m, 4H), 3.46-3.42 (m, 2H), 3.29-3.24(m, 2H), 3.07 (s, 3H), 1.37 (s, 3H), 1.20 (t, 3H, J = 7.1 Hz).

TABLE 1-90 No. structural formula salt ¹H-NMR 324

HCl ¹H-NMR (DMSO-d₆) δ: 12.52 (br s, 1H), 8.91 (s, 1H), 7.44-7.36 (m,2H), 7.22-7.14 (m, 2H), 4.82 (d, 1H, J = 13.5 Hz), 4.47 (s, 2H), 4.35(sep, 1H, J = 6.8 Hz), 4.30 (dd, 1H, J = 13.5, 4.5 Hz), 4.01-3.96 (m,1H), 3.64-3.55 (m, 1H), 3.05 (s, 3H), 1.35 (d, 3H, J = 6.8 Hz), 1.33 (d,3H, J = 6.8 Hz), 1.19 (d, 3H, J = 6.2 Hz). 325

HCl ¹H-NMR (DMSO-d₆) δ: 12.64 (br s, 1H), 8.83 (s, 1H), 7.44-7.35 (m,1H), 7.23-7.15 (m, 1H), 7.05-6.98 (m, 1H), 4.50-4.37 (m, 2H), 4.16-4.07(m, 1H), 3.88-3.76 (m, 1H), 3.40 (t, 2H, J = 7.5 Hz), 3.30-3.19 (m, 1H),3.10 (t, 2H, J = 7.5 Hz), 1.24 (d, 3H, J = 6.6 Hz), 1.20 (t, 3H, J = 7.2Hz). 326

HCl ¹H-NMR (DMSO-d₆) δ: 12.50 (br s, 1H), 8.91 (s, 1H), 7.44-7.37 (m,2H), 7.22-7.15 (m, 2H), 4.80 (d, 1H, J = 13.5 Hz), 4.47 (s, 2H), 4.36(dd, 1H, J = 13.5, 4.6 Hz), 4.00-3.87 (m, 2H), 3.66-3.58 (m, 1H),3.31-3.18 (m, 1H), 3.08 (s, 3H), 1.21 (t, 3H, J = 7.1 Hz), 1.16 (d, 3H,J = 6.4 Hz). 327

HCl ¹H-NMR (DMSO-d₆) δ: 12.42 (br s, 1H), 8.76 (s, 1H), 7.67 (s, 1H),7.36-7.30 (m, 2H), 7.19-7.11 (m, 2H), 4.61 (d, 1H, J = 13.2 Hz), 4.33(dd, 1H, J = 13.2, 3.7 Hz), 4.20 (s, 2H), 3.95-3.83 (m, 1H), 3.88-3.80(m, 1H), 3.22-3.11 (m, 1H), 1.74-1.62 (m, 1H), 1.50-1.36 (m, 1H), 1.20(t, 3H, J = 7.2 Hz), 0.91 (t, 3H, J = 7.4 Hz).

TABLE 1-91 No. structural formula salt ¹H-NMR 328

HCl ¹H-NMR (DMSO-d₆) δ: 12.62 (br s, 1H), 8.84 (s, 1H), 7.45-7.37 (m,2H), 7.23-7.14 (m, 2H), 4.49-4.35 (m, 2H), 4.47 (s, 2H), 4.15-4.07 (m,1H), 3.87-3.75 (m, 1H), 3.31-3.18 (m, 1H), 1.26-1.14 (m, 6H). 329

HCl ¹H-NMR (DMSO-d₆) δ: 12.33 (br s, 1H), 8.82 (s, 1H), 7.67 (s, 1H),7.37-7.30 (m, 2H), 7.18-7.11 (m, 2H), 4.71 (d, 1H, J = 13.9 Hz), 4.32(dd, 1H, J = 13.9, 4.4 Hz), 4.20 (s, 2H), 4.07-3.94 (m, 1H), 3.75-3.69(m, 1H), 3.16-3.04 (m, 1H), 1.97-1.85 (m, 1H), 1.20 (t, 3H, J = 7.1 Hz),0.98 (d, 3H, J = 6.8 Hz), 0.78 (d, 3H, J = 6.8 Hz). 330

HCl ¹H-NMR (DMSO-d₆) δ: 12.52 (br s, 1H), 8.66 (s, 1H), 7.67 (s, 1H),7.37-7.30 (m, 2H), 7.19-7.11 (m, 2H), 4.46-4.33 (m, 2H), 4.20 (s, 2H),4.14-4.04 (m, 1H), 3.86-3.75 (m, 1H), 3.29-3.18 (m, 1H), 1.22 (d, 3H, J= 6.6 Hz), 1.19 (t, 3H, J = 7.2 Hz). 331

HCl ¹H-NMR (DMSO-d₆) δ: 12.68 (br s, 1H), 8.83 (s, 1H), 7.44-7.38 (m,2H), 7.22-7.15 (m, 2H), 4.77 (d, 1H, J = 13.7 Hz), 4.55 (d, 1H, J = 13.7Hz), 4.47 (s, 2H), 4.16-3.03 (m, 5H), 3.44 (sep, 1H, J = 6.6 Hz), 1.63(s, 3H), 1.49 (d, 3H, J = 6.6 Hz), 1.42 (d, 3H, J = 6.6 Hz), 1.09-1.00(m, 3H).

TABLE 1-92 No. structural formula salt ¹H-NMR 332

HCl ¹H-NMR (DMSO-d₆) δ: 12.50 (br s, 1H), 8.95 (s, 1H), 7.44-7.36 (m,2H), 7.22-7.15 (m, 2H), 4.69 (dd, 1H, J = 14.0, 1.5 Hz), 4.47 (s, 2H),4.39 (dd, 1H, J = 14.0, 4.2 Hz), 4.04-3.98 (m, 1H), 3.97-3.92 (m, 1H),3.51-3.43 (m, 1H), 3.26-3.18 (m, 1H), 3.18 (s, 3H), 1.19 (t, 3H, J = 7.2Hz), 1.10 (d, 3H, J = 6.2 Hz). 333

HCl ¹H-NMR (DMSO-d₆) δ: 8.76 (s, 1H), 7.67 (s, 1H), 7.36-7.30 (m, 2H),7.18-7.11 (m, 2H), 4.64 (dd, 1H, J = 13.6, 1.5 Hz), 4.37 (dd, 1H, J =13.6, 4.0 Hz), 4.20 (s, 2H), 4.06-3.97 (m, 1H), 3.95-3.90 (m, 1H),3.51-3.40 (m, 1H), 3.27-3.19 (m, 1H), 3.19 (s, 3H), 1.19 (t, 3H, J = 6.8Hz), 1.08 (d, 3H, J = 6.4 Hz). 334

HCl ¹H-NMR (DMSO-d₆) δ: 12.47 (br s, 1H), 8.96 (s, 1H), 7.44-7.38 (m,2H), 7.22-7.15 (m, 2H), 4.68 (dd, 1H, J = 13.9, 1.3 Hz), 4.47 (s, 2H),4.35 (dd, 1H, J = 13.9, 3.5 Hz), 4.14-4.06 (m, 1H), 3.98-3.93 (m, 1H),3.41 (sep, 1H, J = 6.7 Hz), 3.24 (s, 3H), 1.39 (d, 3H, J = 6.7 Hz), 1.34(d, 3H, J = 6.7 Hz), 1.02 (d, 3H, J = 6.3 Hz). 335

HCl ¹H-NMR (DMSO-d₆) δ: 12.85 (br s, 1H), 8.54 (s, 1H), 7.58-7.50 (m,1H), 7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 4.49 (s, 2H), 4.21 (d, 1H, J= 13.9 Hz), 3.97 (d, 1H, J = 13.9 Hz), 3.07 (s, 3H), 2.91 (s, 6H), 1.97(s, 3H).

TABLE 1-93 No. structural formula salt ¹H-NMR 336

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (br s, 1H), 8.46 (s, 1H), 7.69 (s, 1H),7.50-7.42 (m, 1H), 7.29-7.21 (m, 1H), 7.11-7.05 (m, 1H), 4.22 (s, 2H),4.21 (d, 1H, J = 14.0 Hz), 3.93 (d, 1H, J = 14.0 Hz), 3.07 (s, 3H), 2.89(s, 6H), 1.93 (s, 3H). 337

HCl ¹H-NMR (DMSO-d₆) δ: 12.86 (br s, 1H), 8.83 (s, 1H), 7.45-7.39 (m,2H), 7.23-7.16 (m, 2H), 5.02-4.94 (m, 1H), 4.47 (s, 2H), 4.40-4.29 (m,1H), 3.83-3.56 (m, 4H), 3.26 (s, 3H), 1.64-1.43 (m, 4H), 0.92-0.78 (m,6H).

TABLE 1-94 No. structural formula salt ¹H-NMR 338

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8.92 (s, 1H), 7.44-7.39 (m,2H), 7.21-7.16 (m, 2H), 4.78 (quint, 1H, J = 6.9 Hz), 4.71 (ddd, 1H, J =6.4, 4.0, 1.6 Hz), 4.47 (s, 2H), 3.87 (dd, 1H, J = 13.7, 1.6 Hz), 3.78(dd, 1H, J = 13.7, 4.0 Hz), 3.58 (dq, 1H, J = 6.4, 6.0 Hz), 3.22 (s,3H), 1.19 (d, 3H, J = 6.9 Hz), 1.17 (d, 3H, J = 6.9 Hz), 1.03 (d, 3H, J= 6.0 Hz). 339

¹H-NMR (DMSO-d₆) δ: 8.21 (s, 1H), 7.42-7.39 (m, 2H), 7.20-7.16 (m, 2H),4.85 (quint, 1H, J = 6.6 Hz), 4.71-4.65 (m, 1H), 4.41 (s, 2H), 3.58-3.53(m, 3H), 3.48-3.44 (m, 1H), 3.24 (s, 3H), 1.09 (d, 6H, J = 6.6 Hz). 340

HCl ¹H-NMR (DMSO-d₆) δ: 12.82 (br s, 1H), 8.72 (s, 1H), 7.44-7.41 (m,2H), 7.21-7.17 (m, 2H), 4.77 (sep, 1H, J = 6.6 Hz), 4.65 (ddd, 1H, J =8.2, 4.1, 0.9 Hz), 4.47 (s, 2H), 3.88 (dd, 1H, J = 14.0, 4.1 Hz), 3.76(dd, 1H, J = 14.0, 0.9 Hz), 3.52 (dq, 1H, J = 8.2, 6.2 Hz), 3.03 (s,3H), 1.21 (d, 3H, J = 6.2 Hz), 1.20 (d, 3H, J = 6.6 Hz), 1.17 (d, 3H, J= 6.6 Hz). 341

HCl ¹H-NMR (DMSO-d₆) δ: 8.95 (s, 1H), 7.43-7.38 (m, 2H), 7.21-7.16 (m,2H), 4.68 (dd, 1H, J = 13.8, 1.5 Hz), 4.47 (s, 2H), 4.35 (dd, 1H, J =13.8, 3.9 Hz), 4.10 (quint, 1H, J = 6.6 Hz), 3.96 (ddd, 1H, J = 6.6,3.9, 1.5 Hz), 3.41 (dq, 1H, J = 6.6, 6.4 Hz), 3.24 (s, 3H), 1.39 (d, 3H,J = 6.6 Hz), 1.34 (d, 3H, J = 6.6 Hz), 1.02 (d, 3H, J = 6.4 Hz). 342

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8 72 (s, 1H), 7.45-7.41 (m,3H), 7.22-7.17 (m, 2H), 4.77 (quint, 1H, J = 6.8 Hz), 4.60 (ddd, 1H, J =8.4, 4.2, 0.9 Hz), 4.47 (s, 2H), 3.88 (dd, 1H, J = 14.3, 4.2 Hz), 3.74(dd, 1H, J = 14.3, 0.9 Hz), 3.56 (dq, 1H, J = 8.4, 6.2 Hz), 3.41 (dq,1H, J = 9.5, 7.1 Hz), 2.91 (dq, 1H, J = 9.5, 7.1 Hz), 1.22 (d, 3H, J =6.2 Hz), 1.20 (d, 3H, J = 6.8 Hz), 1.17 (d, 3H, J = 6.8 Hz), 0.75 (t,3H, J = 7.1 Hz).

TABLE 1-95 No. structural formula salt ¹H-NMR 343

HCl ¹H-NMR (DMSO-d₆) δ: 8.85 (s, 1H), 7.43-7.39 (m, 2H), 7.21-7.15 (m,2H), 4.66 (dd, 1H, J = 12.4, 1.5 Hz), 4.48 (sep, 1H, J = 6.6 Hz), 4.47(s, 2H), 4.35 (dd, 1H, J = 13.2, 3.7 Hz), 4.20-4.16 (m, 1H), 3.54 (dd,1H, J = 10.5, 4.1 Hz), 3.45-3.30 (m, 3H), 1.30 (d, 3H, J = 6.6 Hz), 1.28(d, 3H, J = 6.6 Hz), 0.96 (t, 3H, J = 6.9 Hz). 344

¹H-NMR (DMSO-d₆) δ: 12.81 (s, 1H), 8.80 (s, 1H), 7.44-7.39 (m, 2H),7.22-7.16 (m, 2H), 4.99-4.95 (m, 1H), 4.77 (sep, 1H, J = 6.7 Hz), 4.47(s, 2H), 3.84 (dd, 1H, J = 13.7, 3.9 Hz), 3.75 (dd, 1H, J = 13.9, 1.6Hz), 3.63 (dd, 1H, J = 10.2, 6.0 Hz), 3.57 (dd, 1H, J = 10.2, 7.7 Hz),3.25 (s, 3H), 1.16 (d, 3H, J = 6.7 Hz), 1.16 (d, 3H, J = 6.7 Hz). 345

¹H-NMR (DMSO-d₆) δ: 8.10 (s, 1H), 7.41-7.36 (m, 2H), 7.20-7.14 (m, 2H),4.83 (quint, 1H, J = 6.7 Hz), 4.62-4.57 (m, 1H), 4.38 (s, 2H), 3.57-3.44(m, 4H), 3.25 (s, 3H), 1.05 (d, 6H, J = 6.7 Hz). 346

¹H-NMR (DMSO-d₆) δ: 12.44 (br s, 1H), 8.85 (s, 1H), 7.44-7.37 (m, 2H),7.23-7.14 (m, 2H), 4.70- 4.61 (m, 1H), 4.54-4.41 (m, 1H), 4.47 (s, 2H),4.39-4.30 (m, 1H), 4.25-4.14 (m, 1H), 3.53-3.34 (m, 2H), 3.21 (s, 3H),1.30 (d, 3H, J = 6.3 Hz), 1.28 (d, 3H, J = 6.3 Hz). 347

¹H-NMR (DMSO-d₆) δ: 8.02 (br s, 1H), 7.42-7.33 (m, 2H), 7.21-7.13 (m,2H), 4.73-4.59 (m, 1H), 4.38 (s, 2H), 4.34-4.22 (m, 1H), 4.07-3.96 (m,1H), 3.89-3.78 (m, 1H), 3.30-3.05 (m, 2H), 3.24 (s, 3H), 1.13 (d, 3H, J= 7.0 Hz), 1.06 (d, 3H, J = 7.0 Hz).

TABLE 1-96 No. structural formula salt ¹H-NMR 348

HCl ¹H-NMR (DMSO-d₆) δ: 12.81 (br s, 1H), 8.72 (s, 1H), 7.47-7.37 (m,2H), 7.23-7.14 (m, 2H), 4.83- 4.71 (m, 1H), 4.69-4.60 (m, 1H), 4.47 (s,2H), 3.88 (dd, 1H, J = 14.1, 3.7 Hz), 3.81-3.71 (m, 1H), 3.56-3.47 (m,1H), 3.03 (s, 3H), 1.24-1.13 (m, 9H). 349

HCl ¹H-NMR (DMSO-d₆) δ: 12.52 (s, 1H), 8.90 (s, 1H), 7.40 (dd, 2H, J =8.3, 5.6 Hz), 7.17 (dd, 2H, J = 8.3, 8.4 Hz), 4.81 (d, 1H, J = 14.1 Hz),4.46 (s, 2H), 4.38-4.27 (m, 2H), 3.98 (s, 1H), 3.62-3.56 (m, 1H), 3.04(s, 3H), 1.33 (t, 6H, J = 6.0 Hz), 1.18 (d, 3H, J = 7.0 Hz). 350

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (s, 1H), 8.91 (s, 1H), 7.43-7.39 (m, 2H),7.21-7.15 (m, 2H), 4.78 (quint, 1H, J = 6.9 Hz), 4.70 (dd, 1H, J = 6.4,4.2 Hz), 4.47 (s, 2H), 3.86 (d, 1H, J = 13.7 Hz), 3.77 (dd, 1H, J =13.7, 4.2 Hz), 3.58 (dq, 1H, J = 6.4, 6.0 Hz), 3.21 (s, 3H), 1.19 (d,3H, J = 6.9 Hz), 1.17 (d, 3H, J = 6.9 Hz), 1.02 (d, 3H, J = 6.0 Hz). 351

HCl ¹H-NMR (DMSO-d₆) δ: 12.71 (br s, 1H), 8.56 (s, 1H), 7.44-7.36 (m,2H), 7.23-7.14 (m, 2H), 4.70- 4.60 (m, 1H), 4.50-4.38 (m, 1H), 4.47 (s,2H), 4.08-4.02 (m, 1H), 3.61 (dd, 1H, J = 11.1, 3.7 Hz), 3.53 (dd, 1H, J= 11.1, 3.9 Hz), 3.27 (q, 2H, J = 7.4 Hz), 1.75 (d, 3H, J = 6.5 Hz),1.32 (t, 6H, J = 7.0 Hz), 0.82 (t, 3H, J = 7.0 Hz). 352

¹H-NMR (DMSO-d₆) δ: 12.79 (br s, 1H), 8.74 (s, 1H), 7.45-7.38 (m, 2H),7.23-7.15 (m, 2H), 5.32- 5.23 (m, 1H), 4.81-4.65 (m, 2H), 4.47 (s, 2H),3.86-3.64 (m, 3H), 3.60-3.51 (m, 1H), 1.16 (d, 3H, J = 6.7 Hz), 1.15 (d,3H, J = 6.7 Hz).

TABLE 1-97 No. structural formula salt ¹H-NMR 353

HCl ¹H-NMR (DMSO-d₆) δ: 12.77 (br s, 1H), 8.56 (s, 1H), 7.44-7.36 (m,2H), 7.23-7.14 (m, 2H), 4.70- 4.59 (m, 1H), 4.49-4.37 (m, 1H), 4.47 (s,2H), 4.11-4.03 (m, 1H), 3.59-3.46 (m, 2H), 3.11 (s, 3H), 1.75 (d, 3H, J= 6.5 Hz), 1.32 (t, 6H, J = 6.5 Hz). 354

HBr ¹H-NMR (DMSO-D₆) δ: 8.80 (s, 1H), 7.43-7.37 (m, 2H), 7.21-7.14 (m,2H), 4.70-4.64 (m, 1H), 4.55- 4.44 (m, 3H), 4.33 (dd, 1H, J = 13.3, 3.6Hz), 3.99- 3.93 (m, 1H), 3.56 (dd, 1H, J = 11.4, 3.7 Hz), 3.35 (dd, 1H,J = 11.4, 8.1 Hz), 1.28 (d, 3H, J = 6.7 Hz), 1.27 (d, 3H, J = 6.7 Hz).355

HCl ¹H-NMR (DMSO-d₆) δ: 12.78 (br s, 1H), 8.76 (s, 1H), 7.44-7.37 (m,2H), 7.22-7.14 (m, 2H), 4.47 (s, 2H), 4.34 (s, 2H), 3.55 (q, 2H, J = 7.1Hz), 1.36 (s, 6H), 1.19 (t, 3H, J = 7.1 Hz). 356

HCl ¹H-NMR (DMSO-d₆) δ: 12.76 (s, 1H), 8.77 (s, 1H), 7.42-7.36 (m, 2H),7.21-7.14 (m, 2H), 4.71 (ddd, 1H, J = 8.0, 2.2, 2.0 Hz), 4.56 (quint,1H, J = 6.9 Hz), 4.46 (s, 2H), 4.19-4.09 (m, 2H), 3.93 (dd, 1H, J =11.7, 2.2 Hz), 3.45 (s, 3H), 1.29 (d, 3H, J = 6.9 Hz), 1.27 (d, 3H, J =6.9 Hz), 1.04 (d, 3H, J = 6.5 Hz). 357

HCl ¹H-NMR (DMSO-d₆) δ: 12.76 (s, 1H), 8.80 (s, 1H), 7.41 (tt, 2H, J =8.7, 3.1 Hz), 7.18 (tt, 2H, J = 8.9, 2.5 Hz), 4.94-4.88 (m, 1H), 4.46(s, 2H), 4.06 (dd, 1H, J = 13.8, 4.3 Hz), 3.73-3.67 (m, 2H), 3.64-3.52(m, 2H), 3.49-3.27 (m, 3H), 1.63-1.53 (m, 2H), 1.01 (t, 3H, J = 7.0 Hz),0.89 (t, 3H, J = 8.2 Hz).

TABLE 1-98 No. structural formula salt ¹H-NMR 358

HCl ¹H-NMR (DMSO-d₆) δ: 12.90 (br s, 1H), 8.37 (s, 1H), 8.07 (s, 1H),8.00 (s, 1H), 7.45-7.37 (m, 2H), 7.23-7.13 (m, 2H), 5.28-5.18 (m, 1H),4.89-4.60 (m, 3H), 4.44 (s, 2H), 3.98-3.83 (m, 2H), 1.25 (d, 3H, J = 6.7Hz), 1.18 (d, 3H, J = 6.7 Hz). 359

HCl ¹H-NMR (DMSO-d₆) δ: 12.88 (br s, 1H), 8.99 (s, 1H), 8.20 (s, 1H),7.46-7.37 (m, 2H), 7.24-7.14 (m, 2H), 5.48-5.38 (m, 1H), 5.37-5.19 (m,2H), 4.84- 4.72 (m, 1H), 4.45 (s, 2H), 3.96 (d, 2H, J = 3.0 Hz), 1.25(d, 3H, J = 6.7 Hz), 1.17 (d, 3H, J = 6.7 Hz). 360

HCl ¹H-NMR (DMSO-d₆) δ: 12.85 (br s, 1H), 8.75 (s, 1H), 7.45-7.37 (m,2H), 7.22-7.14 (m, 2H), 5.52- 5.41 (m, 1H), 4.81-4.71 (m, 1H), 4.47 (s,2H), 3.98-3.81 (m, 2H), 3.66 (d, 2H, J = 7.0 Hz), 1.29 (s, 9H), 1.21 (d,3H, J = 6.5 Hz), 1.15 (d, 3H, J = 6.5 Hz). 361

HCl ¹H-NMR (DMSO-d₆) δ: 12.94 (s, 1H), 8.80 (s, 1H), 7.43-7.39 (m, 2H),7.21-7.15 (m, 2H), 4.89-4.85 (m, 1H), 4.47 (s, 2H), 3.96 (dd, 1H, J =14.0, 1.5 Hz), 3.87 (dd, 1H, J = 14.0, 3.0 Hz), 3.70 (dd, 1H, J = 10.2,6.7 Hz), 3.62 (dd, 1H, J = 10.2, 7.5 Hz), 3.50-3.41 (m, 2H), 1.49 (s,9H), 1.05 (t, 3H, J = 6.9 Hz). 362

HCl ¹H-NMR (DMSO-d₆) δ: 8.80 (s, 1H), 7.44-7.39 (m, 2H), 7.21-7.16 (m,2H), 4.94-4.89 (m, 1H), 4.47 (s, 2H), 4.06 (dd, 1H, J = 13.6, 4.3 Hz),3.77-3.72 (m, 2H), 3.70-3.46 (m, 5H), 3.38-3.31 (m, 3H), 3.11 (s, 3H),1.60-1.52 (m, 2H), 1.37-1.27 (m, 2H), 0.92 (t, 3H, J = 7.4 Hz).

TABLE 1-99 No. structural formula salt ¹H-NMR 363

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8.82 (s, 1H), 7.46-7.38 (m,2H), 7.24-7.14 (m, 2H), 5.01- 4.91 (br m, 1H), 4.77 (sep, 1H, J = 6.7Hz), 4.47 (s, 2H), 3.88-3.54 (m, 4H), 3.41-3.24 (m, 2H), 1.41 (td, 2H, J= 13.9, 7.2 Hz), 1.17 (d, 3H, J = 6.7 Hz), 1.16 (d, 3H, J = 6.7 Hz),0.74 (t, 3H, J = 7.2 Hz). 364

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8.80 (s, 1H), 7.44-7.37 (m,2H), 7.22-7.13 (m, 2H), 4.99- 4.89 (m, 1H), 4.76 (sep, 1H, J = 7.0),4.46 (s, 2H), 3.88-3.52 (m, 4H), 3.43-3.24 (m, 2H), 1.40-1.29 (m, 2H),1.22-1.09 (m, 8H), 0.69 (t, 3H, J = 7.3 Hz). 365

HCl ¹H-NMR (DMSO-d₆) δ: 12.84 (br s, 1H), 8.83 (s, 1H), 7.46-7.38 (m,2H), 7.23-7.15 (m, 2H), 4.94- 4.71 (m, 2H), 4.47 (s, 2H), 3.85-3.45 (m,5H), 1.21-1.12 (m, 6H), 1.02 (d, 3H, J = 6.0 Hz), 0.96 (d, 3H, J = 6.3Hz). 366

¹H-NMR (DMSO-d₆) δ: 12.77 (s, 1H), 8.80 (s, 1H), 7.45-7.38 (m, 2H),7.23-7.14 (m, 2H), 4.91-4.83 (m, 1H), 4.83-4.73 (m, 2H), 4.47 (s, 2H),3.86 (dd, 1H, J = 14.1, 3.5 Hz), 3.76-3.67 (m, 1H), 3.54-3.43 (m, 1H),1.96-1.71 (m, 2H), 1.19 (d, 3H, J = 7.0 Hz), 1.16 (d, 3H, J = 6.7 Hz).367

HCl ¹H-NMR (DMSO-d₆) δ: 12.42 (br s, 1H), 8.84 (s, 1H), 7.45-7.37 (m,2H), 7.23-7.14 (m, 2H), 4.69- 4.63 (m, 1H), 4.53-4.44 (m, 3H), 4.35 (dd,1H, J = 13.3, 4.0 Hz), 4.18-4.11 (m, 1H), 3.55 (dd, 1H, J = 10.5, 3.6Hz), 3.48-3.39 (m, 2H), 1.30 (d, 3H, J = 6.9 Hz), 1.28 (d, 3H, J = 6.9Hz), 0.95-0.90 (m, 6H).

TABLE 1-100 No. structural formula salt ¹H-NMR 368

HCl ¹H-NMR (DMSO-d₆) δ: 8.78 (s, 1H), 7.44-7.40 (m, 2H), 7.22-7.16 (m,2H), 4.74-4.70 (m, 1H), 4.74 (quint, 1H, J = 7.1 Hz), 4.47 (s, 2H),3.91-3.82 (m, 2H), 3.05 (s, 3H), 1.20 (d, 3H, J = 7.1 Hz), 1.19 (s, 3H),1.18 (d, 3H, J = 7.1 Hz), 1.10 (s, 3H). 369

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (s, 1H), 8.81 (s, 1H), 7.44-7.38 (m, 2H),7.21-7.16 (m, 2H), 4.95 (s, 1H), 4.80-4.73 (m, 1H), 4.47 (s, 2H), 3.85(dd, 1H, J = 13.7, 4.0 Hz), 3.75 (d, 1H, J = 13.7 Hz), 3.67 (dd, 1H, J =10.3, 5.4 Hz), 3.58 (dd, 1H, J = 10.3, 7.7 Hz), 3.45 (dt, 1H, J = 11.4,4.6 Hz), 3.34 (dt, 1H, J = 11.4, 4.8 Hz), 3.20-3.13 (m, 2H), 3.00 (s,3H), 1.64-1.58 (m, 2H), 1.16 (dd, 6H, J = 6.9, 2.4 Hz). 370

HCl ¹H-NMR (DMSO-d₆) δ: 12.78 (br s, 1H), 8.72 (s, 1H), 7.46-7.38 (m,2H), 7.24-7.15 (m, 2H), 4.91- 4.81 (m, 1H), 4.84-4.72 (m, 1H), 4.47 (s,2H), 3.89-3.65 (m, 2H), 3.45-3.35 (m, 1H), 3.20-3.07 (m, 1H), 3.18 (s,3H), 2.07-1.93 (m, 1H), 1.93-1.80 (m, 1H), 1.18 (d, 3H, J = 6.7 Hz),1.16 (d, 3H, J = 6.7 Hz). 371

HCl ¹H-NMR (DMSO-d₆) δ: 12.77 (br s, 1H), 8.75 (s, 1H), 7.47-7.37 (m,2H), 7.24-7.15 (m, 2H), 4.91- 4.73 (m, 2H), 4.47 (s, 2H), 3.90-3.63 (m,2H), 3.58-3.01 (m, 4H), 2.11-1.79 (m, 2H), 1.19 (d, 3H, J = 7.2 Hz),1.16 (d, 3H, J = 7.2 Hz), 1.03 (t, 3H, J = 7.2 Hz). 372

HCl ¹H-NMR (DMSO-d₆) δ: 12.81 (br s, 1H), 8.80 (s, 1H), 7.44-7.36 (m,2H), 7.23-7.14 (m, 2H), 4.93- 4.84 (m, 1H), 4.47 (s, 2H), 4.04 (dd, 1H,J = 13.7, 4.0 Hz), 3.69 (dd, 1H, J = 10.5, 5.6 Hz), 3.66-3.59 (m, 2H),3.53-3.32 (m, 5H), 2.93-2.85 (m, 1H), 0.96-0.69 (m, 4H), 0.93 (d, 3H, J= 6.0 Hz), 0.90 (d, 3H, J = 6.0 Hz).

TABLE 1-101 No. structural formula salt ¹H-NMR 373

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8.80 (s, 1H), 7.44-7.38 (m,2H), 7.22-7.15 (m, 2H), 5.00- 4.91 (m, 1H), 4.77 (sep, 1H, J = 6.9 Hz),4.47 (s, 2H), 3.84 (dd, 1H, J = 13.7, 4.0 Hz), 3.80-3.74 (m, 1H), 3.71(dd, 1H, J = 10.3, 5.8 Hz), 3.65 (dd, 1H, J = 10.3, 7.9 Hz), 3.54-3.32(m, 5H), 1.17 (d, 3H, J = 6.9 Hz), 1.16 (d, 3H, J = 6.9 Hz), 0.92 (d,3H, J = 6.0 Hz), 0.89 (d, 3H, J = 6.0 Hz). 374

HCl ¹H-NMR (DMSO-d₆) δ: 8.89 (s, 1H), 7.70 (d, 1H, J = 2.2 Hz), 7.45 (d,1H, J = 1.8 Hz), 7.44-7.39 (m, 2H), 7.22-7.16 (m, 2H), 6.20 (dd, 1H, J =2.2, 1.8 Hz), 4.86-4.82 (m, 1H), 4.78 (quint, 1H, J = 7.1 Hz), 4.47 (s,2H), 4.26-4.14 (m, 2H), 3.84 (dd, 1H, J = 13.6, 3.6 Hz), 3.68 (dd, 1H, J= 13.6, 0.9 Hz), 2.27-2.20 (m, 2H), 1.18 (d, 3H, J = 7.1 Hz), 1.14 (d,3H, J = 7.1 Hz). 375

HCl ¹H-NMR (DMSO-d₆) δ: 13.19 (br s, 1H), 8.41 (s, 1H), 7.46-7.38 (m,2H), 7.23-7.14 (m, 2H), 4.80- 4.68 (m, 1H), 4.47 (s, 2H), 4.08 (d, 1H, J= 14.1 Hz), 3.81 (d, 1H, J = 14.1 Hz), 2.93 (s, 6H), 2.61- 2.11 (m, 2H),1.19 (d, 3H, J = 7.0 Hz), 1.16 (d, 3H, J = 7.0 Hz), 0.91 (t, 3H, J = 7.2Hz). 376

HCl ¹H-NMR (DMSO-d₆) δ: 13.09 (br s, 1H), 8.30 (s, 1H), 7.70 (s, 1H),7.38-7.28 (m, 2H), 7.19-7.10 (m, 2H), 4.80-4.69 (m, 1H), 4.20 (s, 2H),4.06 (d, 1H, J = 14.1 Hz), 3.78 (d, 1H, J = 14.1 Hz), 2.91 (s, 6H),2.47-2.07 (m, 2H), 1.22-1.12 (m, 6H), 0.87 (t, 3H, J = 7.2 Hz). 377

HCl ¹H-NMR (DMSO-d₆) δ: 12.78 (br s, 1H), 8.96 (s, 1H), 7.43-7.40 (m,2H), 7.21-7.16 (m, 2H), 4.87- 4.80 (m, 1H), 4.80 (quint, 1H, J = 6.6Hz), 4.47 (s, 2H), 4.23 (t, 2H, J = 7.9 Hz), 3.87-3.82 (m, 1H),3.76-3.73 (m, 1H), 3.57-3.46 (m, 2H), 3.33-3.25 (m, 1H), 3.19-3.11 (m,1H), 1.95 (dt, 2H, J = 7.1, 7.9 Hz), 1.22 (d, 3H, J = 6.6 Hz), 1.16 (d,3H, J = 6.6 Hz).

TABLE 1-102 No. structural formula salt ¹H-NMR 378

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (br s, 1H), 8.75 (s, 1H), 7.44-7.40 (m,2H), 7.21-7.16 (m, 2H), 4.88- 4.83 (m, 1H), 4.78 (sep, 1H, J = 6.7 Hz),4.47 (s, 2H), 3.85 (dd, 1H, J = 13.6, 3.6 Hz), 3.73 (dd, 1H, J = 13.6,0.9 Hz), 3.53-3.48 (m, 1H), 3.45-3.31 (m, 4H), 3.29-3.18 (m, 1H), 3.15(s, 3H), 2.04-1.96 (m, 1H), 1.91-1.83 (m, 1H), 1.19 (d, 3H, J = 6.7 Hz),1.16 (d, 3H, J = 6.7 Hz). 379

HCl ¹H-NMR (DMSO-d₆) δ: 12.78 (br s, 1H), 8.91 (s, 1H), 7.44-7.39 (m,2H), 7.22-7.16 (m, 2H), 4.83- 4.81 (m, 1H), 4.79 (sep, 1H, J = 6.7 Hz),4.47 (s, 2H), 3.83 (dd, 1H, J = 13.8, 3.6 Hz), 3.72 (dd, 1H, J = 13.8,1.5 Hz), 3.35-3.22 (m, 2H), 3.18 (s, 3H), 1.81-1.71 (m, 1H), 1.70-1.58(m, 2H), 1.37-1.33 (m, 1H), 1.18 (d, 3H, J = 6.7 Hz), 1.16 (d, 3H, J =6.7 Hz). 380

HCl ¹H-NMR (DMSO-d₆) δ: 12.85 (br s, 1H), 8.83 (s, 1H), 7.46-7.39 (m,2H), 7.23-7.15 (m, 2H), 4.92- 4.83 (br m, 1H), 4.81-4.70 (m, 1H), 4.47(s, 2H), 3.85-3.62 (m, 4H), 3.59-3.48 (m, 1H), 3.26-3.18 (m, 2H), 3.17(s, 3H), 1.21-1.12 (m, 6H), 0.91 (d, 3H, J = 6.5 Hz). 381

HCl ¹H-NMR (DMSO-d₆) δ: 12.85 (br s, 1H), 8.83 (s, 1H), 7.45-7.37 (m,2H), 7.23-7.15 (m, 2H), 4.86- 4.76 (br m, 1H), 4.47 (s, 2H), 4.02 (dd,1H, J = 13.4, 4.2 Hz), 3.77-3.58 (m, 3H), 3.57-3.48 (m, 1H), 3.26-3.19(m, 2H), 3.18 (s, 3H), 2.93-2.84 (m, 1H), 0.92 (d, 3H, J = 6.3 Hz),0.91-0.70 (m, 4H). 382

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (s, 1H), 8.71 (s, 1H), 7.44-7.42 (m, 2H),7.21-7.17 (m, 2H), 4.78 (quint, 1H, J = 6.9 Hz), 4.70 (dd, 1H, J = 9.0,3.7 Hz), 4.47 (s, 2H), 3.87 (dd, 1H, J = 14.5, 3.7 Hz), 3.74 (d, 1H, J =14.5 Hz), 3.32 (ddd, 1H, J = 9.0, 3.6, 6.0 Hz), 2.96 (s, 3H), 1.79-1.70(m, 1H), 1.54-1.43 (m, 1H), 1.19 (dd, 6H, J = 10.9, 6.9 Hz), 0.94 (t,3H, J = 7.5 Hz).

TABLE 1-103 No. structural formula salt ¹H-NMR 383

HCl ¹H-NMR (DMSO-d₆) δ: 12.88 (s, 1H), 7.44-7.40 (m, 2H), 7.21-7.16 (m,2H), 4.86-4.82 (m, 1H), 4.77 (quint, 1H, J = 6.9 Hz), 4.47 (s, 2H),3.83- 3.78 (m, 2H), 3.47-3.42 (m, 1H), 3.18 (s, 3H), 1.53-1.47 (m, 1H),1.33-1.25 (m, 1H), 1.19 (d, 3H, J = 6.9 Hz), 1.17 (d, 3H, J = 6.9 Hz),0.87 (t, 3H, J = 7.5 Hz). 384

HCl ¹H-NMR (DMSO-d₆) δ: 12.82 (br s, 1H), 8.81 (s, 1H), 7.46-7.36 (m,2H), 7.23-7.15 (m, 2H), 4.93- 4.86 (m, 1H), 4.47 (s, 2H), 4.04 (dd, 1H,J = 13.2, 4.2 Hz), 3.75-3.57 (m, 3H), 3.39-3.25 (m, 3H), 3.10 (s, 3H),2.92-2.87 (m, 1H), 0.93 (d, 3H, J = 5.8 Hz), 0.91-0.67 (m, 4H). 385

HCl ¹H-NMR (DMSO-d₆) δ: 12.84 (br s, 1H), 8.82 (s, 1H), 7.45-7.38 (m,2H), 7.23-7.15 (m, 2H), 5.00- 4.92 (br m, 1H), 4.83-4.72 (m, 1H), 4.47(s, 2H), 3.89-3.59 (m, 4H), 3.41-3.24 (m, 3H), 3.09 (s, 3H), 1.17 (d,3H, J = 6.7 Hz), 1.15 (d, 3H, J = 6.7 Hz), 0.93 (d, 3H, J = 6.3 Hz). 386

HCl ¹H-NMR (DMSO-d₆) δ: 12.69 (br s, 1H), 8.56 (s, 1H), 7.66 (s, 1H),7.39-7.30 (m, 2H), 7.19-7.11 (m, 2H), 4.83-4.71 (m, 1H), 4.63-4.54 (m,1H), 4.20 (s, 2H), 3.86 (dd, 1H, J = 14.1. 4.2 Hz), 3.78-3.70 (m, 1H),3.55-3.45 (m, 1H), 3.02 (s, 3H), 1.23-1.14 (m, 9H). 387

HCl ¹H-NMR (DMSO-d₆) δ: 12.68 (br s, 1H), 8.74 (s, 1H), 7.68 (s, 1H),7.37-7.30 (m, 2H), 7.19-7.11 (m, 2H), 4.84-4.73 (m, 1H), 4.69-4.63 (m,1H), 4.20 (s, 2H), 3.89-3.81 (m, 1H), 3.76 (dd, 1H, J = 13.7, 4.0 Hz),3.60-3.52 (m, 1H), 3.22 (s, 3H), 1.21-1.15 (m, 6H), 1.00 (d, 3H, J = 6.0Hz).

TABLE 1-104 No. structural formula salt ¹H-NMR 388

HCl ¹H-NMR (DMSO-d₆) δ: 8.74 (s, 1H), 7.68 (s, 1H), 7.37-7.31 (m, 2H),7.18-7.11 (m, 2H), 4.84-4.73 (m, 1H), 4.69-4.63 (m, 1H), 4.20 (s, 2H),3.89-3.81 (m, 1H), 3.76 (dd, 1H, J = 13.7, 4.0 Hz), 3.60-3.51 (m, 1H),3.22 (s, 3H), 1.21-1.14 (m, 6H), 1.00 (d, 3H, J = 6.0 Hz). 389

HCl ¹H-NMR (DMSO-d₆) δ: 12.81 (s, 1H), 8.73 (s, 1H), 7.45-7.42 (m, 2H),7.21-7.18 (m, 2H), 4.82- 4.75 (m, 1H), 4.65 (dd, 1H, J = 9.1, 2.6 Hz),4.47 (s, 3H), 3.87 (dd, 1H, J = 13.3, 3.8 Hz), 3.74 (d, 1H, J = 13.3Hz), 3.39-3.27 (m, 2H), 2.77-2.73 (m, 1H), 1.79-1.70 (m, 1H), 1.51-1.43(m, 1H), 1.20 (d, 3H, J = 6.9 Hz), 1.17 (d, 3H, J = 6.9 Hz), 0.96 (t,3H, J = 7.5 Hz), 0.74 (t, 3H, J = 6.9 Hz). 390

HCl ¹H-NMR (DMSO-d₆) δ: 12.72 (s, 1H), 7.44-7.42 (m, 2H), 7.21-7.17 (m,2H), 4.62 (d, 1H, J = 5.6 Hz), 4.47 (s, 2H), 4.05 (dd, 1H, J = 13.9, 3.8Hz), 3.57 (d, 1H, J = 13.3 Hz), 3.47-3.45 (m, 1H), 3.34 (dd, 1H, J =9.3, 6.9 Hz), 2.94 (dd, 1H, J = 7.7, 3.6 Hz), 2.86 (dd, 1H, J = 9.3, 7.3Hz), 1.55-1.38 (m, 2H), 0.94 (t, 3H, J = 7.0 Hz), 0.78 (t, 3H, J = 6.5Hz), 0.42-0.36 (m, 1H), 0.34-0.27 (m, 2H), 0.24- 0.20 (m, 1H). 391

HCl ¹H-NMR (DMSO-d₆) δ: 12.90 (s, 1H), 8.86 (s, 1H), 7.47-7.37 (m, 2H),7.23-7.15 (m, 2H), 4.81- 4.65 (m, 1H), 4.47 (s, 2H), 4.41 (d, 1H, J =12.1 Hz), 4.25 (d, 1H, J = 12.1 Hz), 4.06 (d, 1H, J = 14.1 Hz), 3.81 (d,1H, J = 14.1 Hz), 3.75-3.63 (m, 2H), 3.62-3.36 (m, 2H), 3.21 (s, 3H),3.11-2.73 (m, 6H), 1.16 (d, 3H, J = 6.8 Hz), 1.10 (d, 3H, J = 6.8 Hz).392

HCl ¹H-NMR (DMSO-d₆) δ: 13.04 (s, 1H), 8.69 (s, 1H), 7.46-7.38 (m, 2H),7.23-7.14 (m, 2H), 4.76-4.62 (m, 1H), 4.48 (s, 2H), 4.18-4.04 (m, 1H),3.98 (d, 1H, J = 13.5 Hz), 3.94-3.82 (m, 2H), 3.78 (d, 1H, J = 13.5 Hz),3.70-3.57 (m, 1H), 2.50-2.22 (m, 2H), 2.15-2.00 (m, 2H), 1.16 (t, 6H, J= 6.8 Hz), 1.03 (t, 3H, J = 7.5 Hz).

TABLE 1-105 No. structural formula salt ¹H-NMR 393

HCl ¹H-NMR (DMSO-d₆) δ: 8.80 (s, 1H), 8.16 (t, 1H, J = 5.5 Hz), 7.67 (s,1H), 7.38-7.28 (m, 2H), 7.19- 7.10 (m, 2H), 4.76-4.63 (m, 1H), 4.20 (s,2H), 4.17 (d, 1H, J = 11.9 Hz), 4.12 (d, 1H, J = 11.9 Hz), 4.03 (d, 1H,J = 13.9 Hz), 3.76 (d, 1H, J = 13.9 Hz), 3.40 (s, 3H), 3.21-2.92 (m,2H), 1.13 (d, 3H, J = 6.8 Hz), 1.10 (d, 3H, J = 6.8 Hz), 0.99 (t, 3H, J= 7.5 Hz). 394

HCl ¹H-NMR (DMSO-d₆) δ: 8.88 (s, 1H), 8.17 (t, 1H, J = 5.1 Hz), 7.66 (s,1H), 7.37-7.29 (m, 2H), 7.19- 7.10 (m, 2H), 4.76-4.64 (m, 1H), 4.33-4.16(m, 2H), 4.20 (s, 2H), 4.04 (d, 1H, J = 13.9 Hz), 3.78 (d, 1H, J = 13.9Hz), 3.72-3.66 (m, 2H), 3.57-3.50 (m, 2H), 3.25 (s, 3H), 3.20-2.96 (m,2H), 1.14 (d, 3H, J = 6.8 Hz), 1.10 (d, 3H, J = 6.8 Hz), 1.04 (t, 3H, J= 7.3 Hz). 395

HCl ¹H-NMR (DMSO-d₆) δ: 12.50 (br s, 1H), 8.95 (s, 1H), 7.44-7.36 (m,2H), 7.22-7.15 (m, 2H), 4.69 (dd, 1H, J = 14.0, 1.5 Hz), 4.47 (s, 2H),4.39 (dd, 1H, J = 14.0, 4.2 Hz), 4.04-3.98 (m, 1H), 3.97-3.92 (m, 1H),3.51-3.43 (m, 1H), 3.26-3.18 (m, 1H), 3.18 (s, 3H), 1.19 (t, 3H, J = 7.2Hz), 1.10 (d, 3H, J = 6.2 Hz). 396

HCl ¹H-NMR (DMSO-d₆) δ: 12.92 (s, 1H), 8.77 (s, 1H), 7.47-7.37 (m, 2H),7.23-7.14 (m, 2H), 4.79- 4.66 (m, 1H), 4.47 (s, 2H), 4.28 (d, 1H, J =11.9 Hz), 4.12 (d, 1H, J = 11.9 Hz), 4.06 (d, 1H, J = 14.3 Hz), 3.82 (d,1H, J = 14.3 Hz), 3.47-3.29 (m, 5H), 3.05-2.78 (m, 3H), 1.16 (d, 3H, J =7.1 Hz), 1.12 (d, 3H, J = 7.1 Hz), 1.08-0.97 (m, 3H). 397

HCl ¹H-NMR (DMSO-d₆) δ: 12.93 (s, 1H), 8.85 (s, 1H), 7.48-7.34 (m, 2H),7.24-7.13 (m, 2H), 4.77- 4.65 (m, 1H), 4.47 (s, 2H), 4.38 (d, 1H, J =11.9 Hz), 4.23 (d, 1H, J = 11.9 Hz), 4.06 (d, 1H, J = 14.3 Hz), 3.82 (d,1H, J = 14.3 Hz), 3.73-3.24 (m, 6H), 3.19 (s, 3H), 3.06-2.84 (m, 3H),1.16 (d, 3H, J = 6.6 Hz), 1.12 (d, 3H, J = 6.6 Hz), 1.07-0.94 (m, 3H).

TABLE 1-106 No. structural formula salt ¹H-NMR 398

HCl ¹H-NMR (DMSO-d₆) δ: 12.69 (br s, 1H), 8.78 (s, 1H), 7.44-7.36 (m,2H), 7.22-7.14 (m, 2H), 4.84- 4.79 (m, 1H), 4.47 (s, 2H), 4.46-4.37 (m,1H), 4.22-4.13 (m, 2H), 4.01 (dd, 1H, J = 11.9, 2.2 Hz), 3.49-3.39 (m,2H), 3.46 (s, 3H), 3.14 (s, 3H), 1.33 (d, 3H, J = 6.9 Hz), 1.30 (d, 3H,J = 6.9 Hz). 399

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (s, 1H), 8.73 (s, 1H), 7.47-7.39 (m, 2H),7.23-7.15 (m, 2H), 4.60- 4.52 (m, 1H), 4.47 (s, 2H), 4.06 (dd, 1H, J =14.1 4.0 Hz), 3.65-3.55 (m, 2H), 3.47-3.36 (m, 1H), 3.02-2.88 (m, 2H),1.16 (d, 3H, J = 6.2 Hz), 0.94- 0.82 (m, 3H), 0.79 (t, 3H, J = 7.3 Hz),0.75-0.64 (m, 1H). 400

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (s, 1H), 8.72 (s, 1H), 7.47-7.39 (m, 2H),7.24-7.15 (m, 2H), 4.84- 4.71 (m, 1H), 4.60 (dd, 1H, J = 8.6, 2.6 Hz),4.47 (s, 2H), 3.88 (dd, 1H, J = 14.3, 4.0 Hz), 3.75 (d, 1H, J = 13.9Hz), 3.58-3.53 (m, 1H), 3.46-3.34 (m, 1H), 2.97-2.85 (m, 1H), 1.26-1.14(m, 9H), 0.75 (t, 3H, J = 6.9 Hz). 401

HCl ¹H-NMR (DMSO-d₆) δ: 8.72 (s, 1H), 7.47-7.39 (m, 2H), 7.24-7.15 (m,2H), 4.60-4.53 (m, 1H), 4.47 (s, 2H), 4.11 (dd, 1H, J = 14.1, 4.2 Hz),3.75 (d, 1H, J = 13.5 Hz), 3.65-3.37 (m, 4H), 3.00-2.90 (m, 1H), 1.22(d, 3H, J = 5.2 Hz), 1.16 (t, 3H, J = 7.1 Hz), 0.77 (t, 3H, J = 6.9 Hz).402

HCl ¹H-NMR (DMSO-d₆) δ: 12.90 (s, 1H), 8.32 (s, 1H), 7.44-7.40 (m, 2H),7.22-7.17 (m, 2H), 4.81-4.74 (m, 1H), 4.71 (t, 1H, J = 4.8 Hz), 4.47 (s,2H), 3.87 (d, 1H, J = 12.5 Hz), 3.78 (dd, 1H, J = 13.9, 4.2 Hz),3.71-3.65 (m, 1H), 3.57-3.50 (m, 1H), 3.17- 3.10 (m, 1H), 1.19 (t, 6H, J= 7.0 Hz), 1.06 (d, 3H, J = 6.0 Hz), 1.02 (t, 3H, J = 6.9 Hz).

TABLE 1-107 No. structural formula salt ¹H-NMR 403

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (s, 1H), 8.91 (s, 1H), 7.43-7.39 (m, 2H),7.21-7.16 (m, 2H), 4.69 (t, 1H, J = 4.6 Hz), 4.47 (s, 2H), 4.02 (dd, 1H,J = 14.1, 4.4 Hz), 3.84 (d, 1H, J = 13.7 Hz), 3.73-3.67 (m, 1H),3.65-3.58 (m, 1H), 3.56-3.39 (m, 2H), 3.21- 3.15 (m, 1H), 1.16 (t, 3H, J= 7.1 Hz), 1.07 (d, 3H, J = 6.0 Hz), 1.01 (t, 3H, J = 6.9 Hz). 404

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (s, 1H), 8.90 (s, 1H), 7.43-7.39 (m, 2H),7.22-7.16 (m, 2H), 4.66 (t, 1H, J = 4.4 Hz), 4.47 (s, 2H), 3.98 (dd, 1H,J = 13.9, 4.2 Hz), 3.74-3.65 (m, 2H), 3.56-3.48 (m, 1H), 3.20-3.14 (m,1H), 2.92-2.87 (m, 1H), 1.04 (d, 3H, J = 7.0 Hz), 1.02 (t, 3H, J = 7.2Hz), 0.94-0.89 (m, 1H), 0.87-0.80 (m, 2H), 0.75-0.70 (m, 1H). 405

HCl ¹H-NMR (DMSO-d₆) δ: 12.77 (br s, 1H), 8.62 (s, 1H), 7.42-7.38 (m,2H), 7.20-7.16 (m, 2H), 4.77- 4.71 (m, 1H), 4.47 (s, 2H), 4.14 (q, 1H, J= 4.0 Hz), 3.92-3.84 (m, 1H), 3.59 (d, 2H, J = 4.4 Hz), 3.33- 3.26 (m,1H), 3.18 (s, 3H), 1.64 (d, 3H, J = 6.5 Hz), 1.21 (t, 3H, J = 7.1 Hz).406

HCl ¹H-NMR (DMSO-d₆) δ: 12.44 (br s, 1H), 8.89 (s, 1H), 7.44-7.38 (m,2H), 7.22-7.15 (m, 2H), 4.66- 4.60 (m, 1H), 4.56-4.45 (m, 3H), 4.34-4.27(m, 1H), 4.10-4.04 (m, 1H), 3.50-3.36 (m, 2H), 3.24 (s, 3H), 1.89-1.79(m, 1H), 1.73-1.62 (m, 1H), 1.28 (d, 6H, J = 6.9 Hz). 407

HCl ¹H-NMR (DMSO-d₆) δ: 12.77 (br s, 1H), 8.88 (s, 1H), 7.44-7.37 (m,2H), 7.22-7.15 (m, 2H), 4.71- 4.66 (m, 1H), 4.62-4.52 (m, 1H), 4.47 (s,2H), 4.21-4.07 (m, 2H), 3.99 (dd, 1H, J = 11.7, 2.0 Hz), 3.71-3.62 (m,2H), 1.32-1.22 (m, 9H), 1.05 (d, 3H, J = 6.4 Hz).

TABLE 1-108 No. structural formula salt ¹H-NMR 408

HCl ¹H-NMR (DMSO-d₆) δ: 12.73 (s, 1H), 8.72 (s, 1H), 7.44-7.40 (m, 2H),7.22-7.16 (m, 2H), 4.64-4.55 (m, 1H), 4.47 (s, 2H), 4.06 (dd, 1H, J =14.1, 4.2 Hz), 3.66-3.49 (m, 2H), 3.06 (s, 3H), 2.96-2.86 (m, 1H), 1.15(d, 3H, J = 6.0 Hz), 0.96-0.78 (m, 3H), 0.75-0.63 (m, 1H). 409

HCl ¹H-NMR (DMSO-D₆) δ: 12.73 (br s, 1H), 8.71 (s, 1H), 7.47-7.39 (m,2H), 7.24-7.15 (m, 2H), 4.66- 4.56 (m, 1H), 4.47 (s, 2H), 4.11 (dd, 1H,J = 14.1, 4.2 Hz), 3.76 (d, 1H, J = 13.7 Hz), 3.66-3.42 (m, 3H), 3.06(s, 3H), 1.21 (d, 3H, J = 5.7 Hz), 1.16 (t, 3H, J = 7.3 Hz). 410

HCl ¹H-NMR (DMSO-d₆) δ: 12.71 (br s, 1H), 8.71 (s, 1H), 7.47-7.39 (m,2H), 7.24-7.15 (m, 2H), 4.65- 4.57 (m, 1H), 4.47 (s, 2H), 4.10 (dd, 1H,J = 14.1 4.0 Hz), 3.77 (d, 1H, J = 14.8 Hz), 3.59-3.38 (m, 3H), 3.05 (s,3H), 1.60 (dt, 2H, J = 7.4, 7.4 Hz), 1.21 (d, 3H, J = 6.2 Hz), 0.90 (t,3H, J = 7.4 Hz). 411

HCl ¹H-NMR (DMSO-d₆) δ: 12.67 (s, 1H), 8.83 (s, 1H), 7.45-7.37 (m, 2H),7.23-7.14 (m, 2H), 4.81 (t, 1H, J = 6.3 Hz), 4.48 (s, 2H), 4.09-3.99 (m,1H), 3.97- 3.85 (m, 1H), 3.68 (dd, 1H, J = 10.6, 5.7 Hz), 3.55 (dd, 1H,J = 10.6, 7.6 Hz), 3.51-3.30 (m, 2H), 3.19-3.06 (m, 1H), 1.27 (d, 3H, J= 6.6 Hz), 1.17 (t, 3H, J = 6.8 Hz), 1.01 (t, 3H, J = 7.3 Hz). 412

HCl ¹H-NMR (DMSO-d₆) δ: 12.68 (br s, 1H), 8.83 (s, 1H), 7.46-7.37 (m,2H), 7.23-7.15 (m, 2H), 4.85- 4.76 (m, 1H), 4.67-4.57 (m, 1H), 4.48 (s,2H), 4.20-4.10 (m, 1H), 3.64 (dd, 1H, J = 10.5, 5.8 Hz), 3.56-3.32 (m,3H), 1.31-1.18 (m, 9H), 1.02 (t, 3H, J = 7.1 Hz).

TABLE 1-109 No. structural formula salt ¹H-NMR 413

HCl ¹H-NMR (DMSO-d₆) δ: 12.70 (s, 1H), 8.87 (s, 1H), 7.43-7.40 (m, 2H),7.21-7.16 (m, 2H), 4.69 (t, 1H, J = 4.4 Hz), 4.47 (s, 2H), 4.09-4.04 (m,1H), 3.76 (d, 1H, J = 12.9 Hz), 3.66-3.60 (m, 1H), 3.23 (s, 3H), 3.07(s, 3H), 1.04 (d, 3H, J = 6.4 Hz). 414

HCl ¹H-NMR (DMSO-d₆) δ: 12.76 (s, 1H), 8.90 (s, 1H), 7.44-7.39 (m, 2H),7.21-7.17 (m, 2H), 4.69 (t, 1H, J = 4.4 Hz), 4.47 (s, 2H), 4.05-4.00 (m,1H), 3.83 (d, 1H, J = 13.3 Hz), 3.67-3.59 (m, 2H), 3.45-3.39 (m, 1H),3.23 (s, 3H), 1.16 (t, 3H, J = 7.1 Hz), 1.04 (d, 3H, J = 6.0 Hz). 415

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (s, 1H), 8.89 (s, 1H), 7.43-7.40 (m, 2H),7.21-7.16 (m, 2H), 4.66 (t, 1H, J = 4.6 Hz), 4.47 (s, 2H), 3.98 (dd, 1H,J = 13.7, 4.0 Hz), 3.71 (d, 1H, J = 12.5 Hz), 3.59-3.53 (m, 1H), 3.22(s, 3H), 2.94-2.88 (m, 1H), 1.02 (d, 3H, J = 6.0 Hz), 0.95-0.89 (m, 1H),0.85-0.80 (m, 2H), 0.75-0.69 (m, 1H). 416

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (s, 1H), 8.90 (s, 1H), 7.43-7.40 (m, 2H),7.21-7.16 (m, 2H), 4.69 (t, 1H, J = 4.8 Hz), 4.47 (s, 2H), 4.01 (dd, 1H,J = 13.9, 4.2 Hz), 3.83 (d, 1H, J = 12.9 Hz), 3.64-3.58 (m, 1H),3.55-3.48 (m, 1H), 3.41-3.34 (m, 1H), 3.21 (s, 3H), 1.63-1.58 (m, 2H),1.05 (d, 3H, J = 6.0 Hz), 0.91 (t, 3H, J = 7.3 Hz). 417

HCl ¹H-NMR (DMSO-d₆) δ: 8.86 (s, 1H), 7.44-7.35 (m, 2H), 7.19-7.09 (m,2H), 4.86-4.68 (m, 2H), 4.45 (s, 2H), 3.90-3.80 (m, 1H), 3.76-3.67 (m,1H), 3.46- 2.59 (m, 3H), 2.14-1.65 (m, 5H), 1.24 (d, 3H, J = 7.1 Hz),1.19 (d, 3H, J = 7.1 Hz), 1.14-0.98 (m, 6H).

TABLE 1-110 No. structural formula salt ¹H-NMR 418

HCl ¹H-NMR (DMSO-d₆) δ: 8.84 (s, 1H), 7.46-7.36 (m, 2H), 7.23-7.14 (m,2H), 5.21-5.10 (m, 1H), 4.86- 4.73 (m, 1H), 4.47 (s, 2H), 3.84 (d, 2H, J= 2.2 Hz), 3.37-3.11 (m, 4H), 2.87 (d, 2H, J = 7.1 Hz), 1.13 (t, 6H, J =7.3 Hz), 0.99 (t, 3H, J = 7.1 Hz), 0.95 (t, 3H, J = 7.1 Hz). 419

HCl ¹H-NMR (DMSO-d₆) δ: 8.73 (s, 1H), 7.47-7.38 (m, 2H), 7.23-7.15 (m,2H), 4.89-4.76 (m, 1H), 4.47 (s, 2H), 4.20-3.99 (m, 2H), 3.72-3.57 (m,2H), 3.51- 3.32 (m, 2H), 3.18 (s, 3H), 2.15-1.83 (m, 2H), 1.16 (t, 3H, J= 7.3 Hz). 420

HCl ¹H-NMR (DMSO-d₆) δ: 12.75 (br s, 1H), 8.64 (s, 1H), 7.46-7.39 (m,2H), 7.22-7.15 (m, 2H), 4.77- 4.71 (m, 1H), 4.47 (s, 2H), 4.11 (dd, 1H,J = 13.7, 4.0 Hz), 3.77-3.71 (m, 1H), 3.64-3.44 (m, 5H), 3.33 (s, 3H),3.10 (s, 3H), 1.20-1.13 (m, 3H). 421

HCl ¹H-NMR (DMSO-d₆) δ: 12.77 (br s, 1H), 8.61 (s, 1H), 7.46-7.34 (m,2H), 7.24-7.14 (m, 2H), 4.81- 4.69 (m, 1H), 4.47 (s, 2H), 4.15-4.08 (m,1H), 3.90 (td, 1H, J = 13.9, 7.0 Hz), 3.64 (d, 2H, J = 4.2 Hz),3.38-3.21 (m, 3H), 1.65 (d, 3H, J = 7.0 Hz), 1.22 (t, 3H, J = 7.3 Hz),0.89 (t, 3H, J = 6.8 Hz). 422

HCl ¹H-NMR (DMSO-d₆) δ: 12.72 (br s, 1H), 8.55 (s, 1H), 7.45-7.36 (m,2H), 7.23-7.14 (m, 2H), 4.72- 4.61 (m, 1H), 4.49-4.38 (m, 1H), 4.47 (s,2H), 4.09-4.02 (m, 1H), 3.61 (dd, 1H, J = 11.1, 3.0 Hz), 3.54 (dd, 1H, J= 11.1, 3.9 Hz), 3.27 (q, 2H, J = 7.0 Hz), 1.75 (d, 3H, J = 6.6 Hz),1.32 (t, 6H, J = 6.8 Hz), 0.82 (t, 3H, J = 7.0 Hz).

TABLE 1-111 No. structural formula salt ¹H-NMR 423

HCl ¹H-NMR (DMSO-d₆) δ: 8.83 (s, 1H), 7.44-7.35 (m, 2H), 7.18-7.09 (m,2H), 4.84-4.66 (m, 2H), 4.45 (s, 2H), 3.90-3.79 (m, 1H), 3.77-3.64 (m,1H), 3.48- 2.60 (m, 4H), 2.33-2.17 (m, 2H), 2.08-1.77 (m, 2H), 1.24 (d,3H, J = 6.4 Hz), 1.19 (d, 3H, J = 6.6 Hz), 1.12-1.00 (m, 3H), 0.97 (t,3H, J = 7.7 Hz). 424

HCl ¹H-NMR (DMSO-d₆) δ: 9.02 (s, 0.25H), 8.94 (s, 0.75H), 7.46-7.36 (m,2H), 7.23-7.14 (m, 2H), 4.95-4.66 (br m, 2H), 4.47 (s, 2H), 3.92-3.67(m, 2H), 3.53-2.98 (br m, 4H), 2.87-2.53 (br m, 1H), 2.14-1.63 (br m,2H), 1.29-0.86 (br m, 15H). 425

HCl ¹H-NMR (DMSO-d₆) δ: 8.86 (s, 1H), 7.44-7.35 (m, 2H), 7.19-7.08 (m,2H), 4.85-4.69 (m, 2H), 4.45 (s, 2H), 4.22-3.98 (m, 2H), 3.90-3.80 (m.1H), 3.78- 3.68 (m, 1H), 3.13-3.00 (m, 1H), 2.35-2.15 (m, 2H), 2.09-1.93(m, 1H), 1.87-1.71 (m, 1H), 1.24 (d, 3H, J = 6.6 Hz), 1.19 (d, 3H, J =6.8 Hz), 1.07 (t, 6H, J = 6.4 Hz), 0.96 (t, 3H, J = 7.3 Hz). 426

HCl ¹H-NMR (DMSO-d₆) δ: 12.49 (s, 1H), 8.91 (s, 1H), 7.42-7.39 (m, 2H),7.20-7.16 (m, 2H), 4.80 (d, 1H, J = 13.3 Hz), 4.47 (s, 2H), 4.36 (dd,1H, J = 13.7, 4.8 Hz), 3.96-3.89 (m, 2H), 3.65-3.60 (m, 1H), 3.28-3.20(m, 1H), 3.08 (s, 3H), 1.21 (t, 3H, J = 7.1 Hz), 1.16 (d, 3H, J = 6.4Hz). 427

HCl ¹H-NMR (DMSO-d₆) δ: 8.65 (s, 1H), 7.44-7.39 (m, 2H), 7.22-7.16 (m,2H), 4.88-4.84 (m, 1H), 4.46 (s, 2H), 4.08 (dd, 1H, J = 13.5, 3.8 Hz),3.65-3.62 (m, 1H), 3.62 (dq, 1H, J = 13.7, 7.3 Hz), 3.45 (dq, 1H, J =13.7, 7.3 Hz), 3.21 (s, 3H), 3.02-2.97 (m, 1H), 1.93-1.78 (m, 2H), 1.16(t, 3H, J = 7.3 Hz), 1.04 (d, 3H, J = 6.0 Hz).

TABLE 1-112 No. structural formula salt ¹H-NMR 428

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (s, 1H), 8.64 (s, 1H), 7.44-7.40 (m, 2H),7.21-7.17 (m, 2H), 4.91-4.87 (m, 1H), 4.78 (sep, 1H, J = 6.8 Hz), 4.46(s, 2H), 3.84 (dd, 1H, J = 13.5, 3.6 Hz), 3.68 (dd, 1H, J = 13.5, 1.3Hz), 3.22 (s, 3H), 2.99-2.95 (m, 1H), 1.86 (ddd, 1H, J = 14.6, 9.9, 3.1Hz), 1.77 (ddd, 1H, J = 14.6, 10.4, 4.9 Hz), 1.18 (d, 3H, J = 6.8 Hz),1.15 (d, 3H, J = 6.8 Hz), 1.04 (d, 3H, J = 6.0 Hz). 429

HCl ¹H-NMR (DMSO-d₆) δ: 12.77 (br s, 1H), 8.65 (s, 1H), 7.44-7.40 (m,2H), 7.21-7.16 (m, 2H), 4.85- 4.80 (m, 1H), 4.46 (s, 2H), 4.02 (dd, 1H,J = 13.2, 3.7 Hz), 3.54 (dd, 1H, J = 13.2, 0.9 Hz), 3.21 (s, 3H),3.03-2.96 (m, 1H), 2.97-2.91 (m, 1H), 1.85- 1.75 (m, 2H), 1.03 (d, 3H, J= 6.0 Hz), 0.95-0.72 (m, 4H). 430

HCl ¹H-NMR (DMSO-d₆) δ: 12.48 (br s, 1H), 8.95 (s, 1H), 7.45-7.37 (m,2H), 7.23-7.14 (m, 2H), 5.01- 4.90 (m, 1H), 4.56 (sep, 1H, J = 6.8 Hz),4.48 (s, 2H), 4.08-4.01 (m, 1H), 3.55 (dd, 1H, J = 10.5, 3.9 Hz),3.45-3.31 (m, 3H), 1.40 (d, 3H, J = 6.6 Hz), 1.29 (d, 3H, J = 6.8 Hz),1.28 (d, 3H, J = 6.8 Hz), 0.98 (t, 3H, J = 6.9 Hz). 431

HCl ¹H-NMR (DMSO-d₆) δ: 12.50 (br s, 1H), 8.93 (s, 1H), 7.45-7.36 (m,2H), 7.23-7.14 (m, 2H), 4.92 (q, 1H, J = 6.7 Hz), 4.48 (s, 2H),4.04-3.96 (m, 2H), 3.59-3.47 (m, 2H), 3.44-3.31 (m, 2H), 3.22- 3.09 (m,1H), 1.42 (d, 3H, J = 6.7 Hz), 1.20 (t, 3H J = 7.1 Hz), 0.97 (t, 3H, J =6.9 Hz). 432

HCl ¹H-NMR (DMSO-d₆) δ: 8.80-8.74 (m, 1H), 7.68 (s, 1H), 7.38-7.29 (m,2H), 7.20-7.10 (m, 2H), 4.97- 4.55 (m, 2H), 4.20 (s, 2H), 3.92-3.60 (m,2H), 3.60-3.02 (m, 2H), 2.93 (s, 2H), 2.72 (s, 1H), 2.08- 1.59 (m, 5H),1.22 (d, 3H, J = 7.1 Hz), 1.16 (d, 3H, J = 6.4 Hz).

TABLE 1-113 No. structural formula salt ¹H-NMR 433

HCl ¹H-NMR (DMSO-d₆) δ: 8.66 (s, 1H), 7.61 (s, 1H), 7.36-7.27 (m, 2H),7.16-7.04 (m, 2H), 4.84-4.56 (m, 2H), 4.19 (s, 2H), 3.88-3.76 (m, 1H),3.75-3.63 (m, 1H), 3.52-3.14 (m, 2H), 3.03-2.70 (m, 3H), 2.33-2.17 (m,2H), 2.06-1.76 (m, 2H), 1.24 (d, 3H, J = 6.6 Hz), 1.19 (d, 3H, J = 6.6Hz), 0.96 (t, 3H, J = 7.5 Hz). 434

HCl ¹H-NMR (DMSO-d₆) δ: 12.63 (br s, 1H), 8.73 (s, 1H), 7.44-7.41 (m,2H), 7.21-7.17 (m, 2H), 4.60- 4.55 (m, 1H), 4.47 (s, 2H), 4.05 (dd, 1H,J = 13.9, 3.4 Hz), 3.78 (dd, 1H, J = 13.9, 1.1 Hz), 3.63 (dq, 1H, J =13.5, 7.1 Hz), 3.48 (dq, 1H, J = 13.5, 7.1 Hz), 3.18 (dd, 1H, J = 9.9,4.2 Hz), 3.02 (s, 3H), 2.88 (dd, 1H, J = 9.9, 3.4 Hz), 2.11-2.04 (m,1H), 1.16 (t, 3H, J = 7.1 Hz), 1.07 (d, 3H, J = 6.8 Hz). 435

HCl ¹H-NMR (DMSO-d₆) δ: 12.71 (br s, 1H), 8.75 (s, 1H), 7.44-7.41 (m,2H), 7.22-7.17 (m, 2H), 4.79 (sep, 1H, J = 6.8 Hz), 4.60-4.57 (m, 1H),4.46 (s, 2H), 3.82 (dd, 1H, J = 14.3, 3.5 Hz), 3.77 (dd, 1H, J = 14.3,1.3 Hz), 3.16 (dd, 1H, J = 9.9, 4.1 Hz), 2.99 (s, 3H), 2.83 (dd, 1H, J =9.9, 3.3 Hz), 2.06- 2.02 (m, 1H), 1.20 (d, 3H, J = 6.8 Hz), 1.19 (d, 3H,J = 6.8 Hz), 1.08 (d, 3H, J = 6.8 Hz). 436

HCl ¹H-NMR (DMSO-d₆) δ: 12.64 (br s, 1H), 8.73 (s, 1H), 7.44-7.40 (m,2H), 7.21-7.17 (m, 2H), 4.57- 4.54 (m, 1H), 4.46 (s, 2H), 4.01 (dd, 1H,J = 13.7, 3.6 Hz), 3.61 (dd, 1H, J = 13.7, 1.2 Hz), 3.17 (dd, 1H, J =9.9, 4.4 Hz), 3.02 (s, 3H), 2.98-2.92 (m, 1H), 2.88 (dd, 1H, J = 9.9,3.4 Hz), 2.07-1.99 (m, 1H), 1.03 (d, 3H, J = 6.9 Hz), 0.93-0.81 (m, 3H),0.72-0.65 (m, 1H). 437

HCl ¹H-NMR (DMSO-d₆) δ: 12.83 (br s, 1H), 8.65 (s, 1H), 7.46-7.40 (m,2H), 7.22-7.16 (m, 2H), 4.83- 4.71 (m, 2H), 4.47 (s, 2H), 3.93-3.86 (m,1H), 3.79-3.73 (m, 1H), 3.60-3.47 (m, 3H), 3.33 (s, 3H), 3.08 (s, 3H),1.22 (d, 3H, J = 6.9 Hz), 1.18 (d, 3H, J = 6.9 Hz).

TABLE 1-114 No. structural formula salt ¹H-NMR 438

HCl ¹H-NMR (DMSO-d₆) δ: 12.74 (br s, 1H), 8.64 (s, 1H), 7.46-7.39 (m,2H), 7.22-7.15 (m, 2H), 4.76- 4.70 (m, 1H), 4.47 (s, 2H), 4.10-4.02 (m,1H), 3.67-3.60 (m, 1H), 3.60-3.53 (m, 1H), 3.48 (dd, 1H, J = 10.9, 4.0Hz), 3.43 (dd, 1H, J = 10.9, 5.2 Hz), 3.32 (s, 3H), 3.10 (s, 3H),2.96-2.88 (m, 1H), 0.95-0.73 (m, 4H). 439

HCl ¹H-NMR (DMSO-d₆) δ: 12.46 (br s, 1H), 8.87 (s, 1H), 7.45-7.36 (m,2H), 7.23-7.14 (m, 2H), 4.65- 4.56 (m, 1H), 4.47 (s, 2H), 4.38 (dd, 1H,J = 13.7, 3.6 Hz), 4.07-3.98 (m, 1H), 3.91 (td, 1H, J = 13.9, 7.1 Hz),3.48-3.33 (m, 2H), 3.23 (s, 3H), 3.11 (td, 1H, J = 13.9, 7.1 Hz),1.91-1.79 (m, 1H), 1.79-1.67 (m, 1H), 1.20 (t, 3H, J = 7.1 Hz). 440

HCl ¹H-NMR (DMSO-d₆) δ: 12.63 (s, 1H), 8.76 (s, 1H), 7.44-7.40 (m, 2H),7.21-7.16 (m, 2H), 4.66 (dd, 1H, J = 9.7, 4.4 Hz), 4.47 (s, 2H), 3.97(dd, 1H, J = 13.9, 6.2 Hz), 3.92-3.86 (m, 1H), 3.41-3.36 (m, 1H),3.17-3.10 (m, 5H), 2.08-2.01 (m, 1H), 1.87- 1.80 (m, 1H), 1.24 (d, 3H, J= 6.4 Hz), 1.19 (t, 3H, J = 7.1 Hz). 441

HCl ¹H-NMR (DMSO-d₆) δ: 12.77 (s, 1H), 8.64 (s, 1H), 7.44-7.40 (m, 2H),7.22-7.17 (m, 2H). 4.71-4.67 (m, 1H), 4.47 (s, 2H), 4.33-4.27 (m, 1H),3.76 (td, 1H, J = 14.1, 7.1 Hz), 3.43-3.36 (m, 2H), 3.15 (s, 3H),3.12-3.05 (m, 1H), 2.09-2.02 (m, 1H), 1.94- 1.84 (m, 1H), 1.33 (d, 3H, J= 5.2 Hz), 1.14 (t, 3H, J = 7.1 Hz). 442

HCl ¹H-NMR (DMSO-d₆) δ: 12.65 (s, 1H), 8.75 (s, 1H), 7.43-7.40 (m, 2H),7.21-7.17 (m, 2H), 4.67-4.58 (m, 2H), 4.47 (s, 2H), 4.10-4.04 (m, 1H),3.42-3.37 (m, 1H), 3.17 (s, 3H), 3.15-3.09 (m, 1H), 2.05-1.97 (m, 1H),1.82-1.75 (m, 1H), 1.28-1.23 (m, 9H).

TABLE 1-115 No. structural formula salt ¹H-NMR 443

HCl ¹H-NMR (DMSO-d₆) δ: 12.76 (s, 1H), 8.65 (s, 1H), 7.42-7.39 (m, 2H),7.20-7.16 (m, 2H), 4.56-4.51 (m, 2H), 4.47 (s, 2H), 4.09-4.03 (m, 1H),3.63-3.54 (m, 2H), 3.31 (s, 3H), 2.50-2.48 (m, 1H), 2.12-2.06 (m, 1H),1.30 (d, 3H, J = 7.0 Hz), 1.28 (d, 3H, J = 7.0 Hz), 1.09 (d, 3H, J = 6.0Hz). 444

HCl ¹H-NMR (DMSO-d₆) δ: 12.48 (br s, 1H), 8.80 (s, 1H), 7.43-7.38 (m,2H), 7.21-7.16 (m, 2H), 4.55 (dd, 1H, J = 13.2, 1.5 Hz), 4.47 (s, 2H),4.38 (dd, 1H, J = 13.2, 3.5 Hz), 4.08-4.04 (m, 1H), 3.98 (dq, 1H, J =13.5, 7.1 Hz), 3.42-3.37 (m, 1H), 3.20 (s, 3H), 3.06 (dq, 1H, J = 13.5,7.1 Hz), 1.71-1.59 (m, 2H), 1.20 (t, 3H, J = 7.1 Hz), 1.06 (d, 3H, J =6.2 Hz). 445

HCl ¹H-NMR (DMSO-d₆) δ: 8.81 (s, 1H), 7.44-7.39 (m, 2H), 7.21-7.16 (m,2H), 4.57 (dd, 1H, J = 13.2, 1.3 Hz), 4.47 (s, 2H), 4.45 (sep, 1H, J =6.8 Hz), 4.31 (dd, 1H, J = 13.2, 3.3 Hz), 4.11-4.06 (m, 1H), 3.50-3.45(m, 1H), 3.19 (s, 3H), 1.68-1.57 (m, 2H), 1.31 (d, 3H, J = 6.8 Hz), 1.28(d, 3H, J = 6.8 Hz), 1.08 (d, 3H, J = 6.2 Hz). 446

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (br s, 1H), 8.75 (s, 1H), 7.45-7.39 (m,2H), 7.22-7.16 (m, 2H), 4.86- 4.75 (m, 2H), 4.47 (s, 2H), 3.86-3.80 (m,1H), 3.76 (dd, 1H, J = 13.3, 3.6 Hz), 3.61 (dd, 1H, J = 11.7, 2.8 Hz),3.58-3.51 (m, 1H), 3.30 (s, 3H), 3.18 (s, 3H), 2.97 (dd, 1H, J = 11.7,2.8 Hz), 1.20 (d, 3H, J = 6.9 Hz), 1.17 (d, 3H, J = 6.9 Hz). 447

HCl ¹H-NMR (DMSO-d₆) δ: 12.47 (br s, 1H), 8.99 (s, 1H), 7.44-7.38 (m,2H), 7.22-7.15 (m, 2H), 4.73 (d, 1H, J = 13.7 Hz), 4.47 (s, 2H), 4.34(dd, 1H, J = 13.7, 4.4 Hz), 4.23-4.14 (m, 1H), 4.05-4.00 (m, 1H), 3.46(dd, 1H, J = 9.7, 8.1 Hz), 3.37 (dd, 1H, J = 9.7, 5.2 Hz), 3.30 (s, 3H),2.22-2.11 (m, 1H), 1.38 (d, 3H, J = 6.9 Hz), 1.34 (d, 3H, J = 6.9 Hz),0.60 (d, 3H, J = 7.3 Hz).

TABLE 1-116 No. structural formula salt ¹H-NMR 448

HCl ¹H-NMR (DMSO-d₆) δ: 12.42 (br s, 1H), 9.00 (s, 1H), 7.44-7.37 (m,2H), 7.22-7.14 (m, 2H), 4.76- 4.68 (m, 1H), 4.47 (s, 2H), 4.37 (dd, 1H,J = 14.1, 4.0 Hz), 4.07-3.96 (m, 1H), 3.93-3.86 (m, 1H), 3.38-3.28 (m,2H), 3.26 (s, 3H), 3.11-2.99 (m, 1H), 2.05-1.95 (m, 1H), 1.19 (t, 3H, J= 7.1 Hz), 0.81 (d, 3H, J = 6.9 Hz). 449

HCl ¹H-NMR (DMSO-d₆) δ: 12.50 (s, 1H), 8.57 (s, 1H), 7.43-7.38 (m, 2H),7.21-7.16 (m, 2H), 4.65-4.59 (m, 1H), 4.47 (s, 2H), 4.30-4.24 (m, 1H),4.01-3.96 (m, 1H), 3.33-3.24 (m, 2H), 3.11 (s, 3H), 1.92-1.86 (m, 1H),1.70 (d, 3H, J = 6.4 Hz), 1.66-1.59 (m, 1H), 1.38 (d, 3H, J = 6.9 Hz),1.33 (d, 3H, J = 6.9 Hz). 450

HCl ¹H-NMR (DMSO-d₆) δ: 12.52 (s, 1H), 8.93 (s, 1H), 7.43-7.38 (m, 2H),7.21-7.16 (m, 2H), 4.88-4.84 (m, 1H), 4.48 (s, 2H), 4.08-4.02 (m, 1H),3.83 (t, 1H, J = 7.1 Hz), 3.44-3.37 (m, 2H), 3.23 (s, 3H), 3.04-2.96 (m,1H), 1.84-1.73 (m, 2H), 1.41 (d, 3H, J = 6.9 Hz), 1.19 (t, 3H, J = 7.0Hz). 451

HCl ¹H-NMR (DMSO-d₆) δ: 12.50 (s, 1H), 8.95 (s, 1H), 7.42-7.38 (m, 2H),7.21-7.16 (m, 2H), 4.91 (dd, 1H, J = 12.7, 5.8 Hz), 4.61-4.54 (m, 1H),4.48 (s, 2H), 3.88 (d, 1H, J = 8.9 Hz), 3.50-3.39 (m, 2H), 3.24 (s, 3H),1.91-1.85 (m, 1H), 1.69-1.61 (m, 1H), 1.39 (d, 3H, J = 6.9 Hz), 1.28 (d,3H, J = 6.4 Hz), 1.26 (d, 3H, J = 6.4 Hz). 452

HCl ¹H-NMR (DMSO-d₆) δ: 12.70 (s, 1H), 8.65 (s, 1H), 7.42-7.38 (m, 2H),7.22-7.15 (m, 2H), 4.75-4.70 (m, 1H), 4.47 (s, 2H), 4.08-3.96 (m, 2H),3.37-3.31 (m, 2H), 3.20 (s, 3H), 3.15-3.07 (m, 1H), 1.94-1.87 (m, 1H),1.68-1.58 (m, 4H), 1.20 (t, 3H, J = 7.1 Hz).

TABLE 1-117 No. structural formula salt ¹H-NMR 453

HCl ¹H-NMR (DMSO-d₆) δ: 12.72 (br s, 1H), 8.81 (s, 1H), 7.45-7.39 (m,2H), 7.23-7.15 (m, 2H), 4.95- 4.88 (m, 1H), 4.78 (sep, 1H, J = 6.9 Hz),4.47 (s, 2H), 3.81 (dd, 1H, J = 13.5, 3.4 Hz), 3.74-3.65 (m, 1H),3.58-3.48 (m, 1H), 3.03 (s, 3H), 1.88-1.80 (m, 1H), 1.78-1.68 (m, 1H),1.19 (d, 3H, J = 6.9 Hz), 1.16 (d, 3H, J = 6.9 Hz), 1.07 (d, 3H, J = 6.0Hz). 454

HCl ¹H-NMR (DMSO-d₆) δ: 12.67 (br s, 1H), 8.82 (s, 1H), 7.45-7.38 (m,2H), 7.23-7.14 (m, 2H), 4.93- 4.83 (m, 1H), 4.47 (s, 2H), 4.05 (dd, 1H,J = 13.5, 3.8 Hz), 3.71-3.42 (m, 4H), 3.05 (s, 3H), 1.95-1.86 (m, 1H),1.82-1.71 (m, 1H), 1.16 (t, 3H, J = 7.1 Hz), 1.09 (d, 3H, J = 6.0 Hz).455

HCl ¹H-NMR (DMSO-d₆) δ: 8.82 (s, 1H), 7.43-7.40 (m, 2H), 7.21-7.16 (m,2H), 4.88-4.83 (m, 1H), 4.46 (s, 2H), 3.98 (dd, 1H, J = 13.3, 3.6 Hz),3.53 (dd, 1H, J = 13.3, 1.8 Hz), 3.52-3.46 (m, 1H), 3.02 (s, 3H),2.98-2.93 (m, 1H), 1.86 (ddd, 1H, J = 14.3, 6.2, 2.6 Hz), 1.71 (ddd, 1H,J = 14.3, 8.8, 7.9 Hz), 1.08 (d, 3H, J = 6.0 Hz), 0.94-0.79 (m, 3H),0.75-0.70 (m, 1H). 456

HCl ¹H-NMR (DMSO-d₆) δ: 8.66 (s, 0.7H), 8.50 (s, 0.3H), 7.70-7.64 (m,1.0H), 7.37-7.30 (m, 2.0H), 7.19-7.11 (m, 2.0H), 4.70-4.62 (m, 0.3H),4.59- 4.51 (m, 0.7H), 4.44-4.34 (m, 0.7H), 4.20 (s, 2.0H), 4.08-3.99 (m,1.0H), 3.80-3.70 (m, 0.3H), 3.69-3.47 (m, 3.0H), 2.80 (s, 2.1H), 2.69(s, 0.9H), 2.12-1.86 (m, 4.3H), 1.83-1.73 (m, 0.7H), 1.22- 1.12 (m,3.0H), 1.05 (d, 0.9H, J = 6.4 Hz), 1.00 (d, 2.1H, J = 6.4 Hz). 457

HCl ¹H-NMR (DMSO-d₆) δ: 12.80 (br s, 1H), 8.82 (s, 1H), 7.44-7.39 (m,2H), 7.21-7.16 (m, 2H), 4.77 (sep, 1H, J = 6.9 Hz), 4.69-4.65 (m, 1H),4.47 (s, 2H), 3.86 (d, 2H, J = 2.8 Hz), 3.37 (d, 2H, J = 5.2 Hz), 3.28(s, 3H), 2.22-2.15 (m, 1H), 1.21 (d, 3H, J = 6.9 Hz), 1.18 (d, 3H, J =6.9 Hz), 0.66 (d, 3H, J = 6.9 Hz).

TABLE 1-118 No. structural formula salt ¹H-NMR 458

HCl ¹H-NMR (DMSO-d₆) δ: 8.63 (s, 0.67H), 8.46 (s, 0.33H), 7.71-7.61 (m,1H), 7.39-7.28 (m, 2H), 7.21-7.10 (m, 2H), 4.67-4.31 (m, 2H), 4.26-4.16(m, 2H), 4.07-3.42 (br m, 2H), 3.03-2.56 (br m, 4H), 2.14-1.59 (m, 5H),1.28-0.60 (m, 7H). 459

HCl ¹H-NMR (DMSO-d₆) δ: 9.18-8.08 (m, 1H), 7.49- 7.10 (m, 4H), 5.28-3.81(m, 6H), 3.07-2.45 (m, 4H), 2.36-1.64 (m, 5H), 1.38-0.32 (m, 7H). 460

HCl ¹H-NMR (DMSO-d₆) δ: 12.72 (br s, 1H), 8.92-8.63 (m, 1H), 7.47-7.37(m, 2H), 7.24-7.13 (m, 2H), 4.80-4.19 (m, 4H), 4.10-3.39 (m, 2H),3.04-2.48 (m, 4H), 2.15-1.61 (m, 5H), 1.18-0.59 (m, 7H). 461

HCl ¹H-NMR (DMSO-d₆) δ: 8.63 (s, 1H), 7.68 (s, 1H), 7.37-7.29 (m, 2H),7.19-7.10 (m, 2H), 4.90-4.65 (m, 2H), 4.61-4.45 (m, 1H), 4.20 (s, 2H),3.89-3.55 (m, 2H), 2.81 (s, 3H), 2.00 (s, 3H), 1.95-1.76 (m, 2H),1.29-1.11 (br m, 6H), 1.02 (d, 3H, J = 7.1 Hz).

TABLE 1-119 No. structural formula salt ¹H-NMR 462

HCl ¹H-NMR (DMSO-d₆) δ: 8.63 (s, 0.75H), 8.44 (s, 0.25H), 7.69-7.63 (m,1H), 7.39-7.29 (m, 2H), 7.19-7.10 (m, 2H), 4.85-3.97 (m, 3H), 4.20 (s,2H), 3.85-3.54 (m, 2H), 2.81 (s, 2.25H), 2.72 (s, 0.75H), 2.06-1.61 (m,5H), 1.33-1.08 (m, 6H), 1.08-0.93 (m, 3H). 463

HCl ¹H-NMR (DMSO-d₆) δ: 12.58 (br s, 1.0H), 8.62 (s, 0.9H), 8.58 (s,0.1H), 7.68 (s, 0.9H), 7.67 (s, 0.1H), 7.36-7.30 (m, 2.0H), 7.18-7.11(m, 2.0H), 4.76-4.65 (m, 1.0H), 4.57-4.49 (m, 1.0H), 4.20 (s, 2.0H),3.99-3.93 (m, 1.0H), 3.75-3.59 (m, 1.9H), 3.59-3.38 (m, 1.1H), 2.80 (s,2.7H), 2.58 (s, 0.3H), 1.98 (s, 2.7H), 1.92-1.83 (m, 2.3H), 1.22-1.13(m, 3.3H), 1.03 (d, 2.7H, J = 6.9 Hz). 464

HCl ¹H-NMR (DMSO-d₆) δ: 12.72 (br s, 1H), 8.81 (s, 1H), 7.44-7.39 (m,2H), 7.21-7.16 (m, 2H), 4.65- 4.62 (m, 1H), 4.47 (s, 2H), 4.09 (dd, 1H,J = 13.7, 4.0 Hz), 3.82 (dd, 1H, J = 13.7, 0.8 Hz), 3.58 (dq, 1H, J =13.3, 7.3 Hz), 3.53 (dq, 1H, J = 13.3, 7.3 Hz), 3.37 (dd, 1H, J = 9.7,4.8 Hz), 3.32 (dd, 1H, J = 9.7, 6.4 Hz), 3.26 (s, 3H), 2.24-2.17 (m,1H), 1.17 (t, 3H, J = 7.3 Hz), 0.72 (d, 3H, J = 6.9 Hz). 465

HCl ¹H-NMR (DMSO-d₆) δ: 12.71 (br s, 1H), 8.81 (s, 1H), 7.43-7.39 (m,2H), 7.21-7.16 (m, 2H), 4.64- 4.61 (m, 1H), 4.47 (s, 2H), 4.01 (dd, 1H,J = 13.7, 4.0 Hz), 3.72 (dd, 1H, J = 13.7, 1.2 Hz), 3.34-3.29 (m, 2H),3.27 (s, 3H), 2.98-2.92 (m, 1H), 2.20-2.14 (m, 1H), 0.90-0.79 (m, 4H),0.67 (d, 3H, J = 6.9 Hz).

Experimental Example 1

The following explains evaluation methods of the HIV integraseinhibitory activity of the compound of the present invention.

(i) Construction of Recombinant Integrase Gene Expression System

A full-length gene sequence (Accession No.: M19921) of HIV-1 pNL4-3integrase was inserted into restriction enzyme Nde I and Xho I sites ofplasmid pET21a(+) (manufactured by Novagen) to construct an integraseexpression vector pET21a-IN-Wild type.

(ii) Production and Purification of Integrase Protein

Escherichia coli recombinant BL21(DE3) transformed with plasmidpET21a-IN-Wild type obtained in (i) was shake cultured at 30° C. in aliquid medium containing ampicillin. When the culture reached thelogarithmic growth phase, isopropyl-β-D-thiogalactopyranoside was addedto promote expression of integrase gene. The culture was continued for 5hr to promote accumulation of the integrase protein. The recombinant E.coli was collected in pellets by centrifugal separation and preserved at−80° C.

This Escherichia coli was suspended in Lysis buffer (50 mM Tris-HCl (pH7.6), 10 mM MgCl₂, 5 mM DTT), and disrupted by repeating treatments ofpressurization and depressurization, and insoluble fraction wascollected by centrifugation at 4° C., 18,000 rpm for 60 min. This wassuspended in Lysis buffer containing a protease inhibitor, 1.25 mMsodium chloride and 10 mM CHAPS were added, and the mixture was stirredat 4° C. for 30 min. Water-soluble fraction was collected bycentrifugation at 4° C., 9,000 rpm for 30 min. The obtained fraction wasdiluted with a column buffer (50 mM Tris-HCl (pH 7.6), 1 mM DTT, 10%Glycerol, 10 mM CHAPS) to 5-fold, and the mixture was applied to heparincolumn (HiPrep 16/10 Heparin FF column: manufactured by GE HealthcareBio-Sciences). Using a column buffer containing 1M NaCl, a protein waseluted with 0-1M NaCl concentration gradient, and an eluted fractioncontaining an integrase protein was collected. The obtained fraction wasdiluted 5-fold with a column buffer (50 mM Tris-HCl (pH 7.6), 1 mM DTT,10% Glycerol, 10 mM CHAPS), and the mixture was applied to cationexchange column (Mono-S column: manufactured by GE HealthcareBio-Sciences). Using a column buffer containing 1M NaCl, a protein waseluted with 0-1M NaCl concentration gradient, and an eluted fractioncontaining an integrase protein was collected. The obtained fractions ofthe integrase protein were collected, and preserved at −80° C.

(iii) Preparation of DNA Solution

The following DNA synthesized by FASMAC was dissolved in TE buffer (10mM Tris-hydrochloric acid (pH 8.0), 1 mM EDTA) and mixed with donor DNA,target DNA, and each complementary strand (+ and − strands) to 1 μM. Themixture was heated at 95° C. for 5 min, 80° C. for 10 min, 70° C. for 10min, 60° C. for 10 min, 50° C. for 10 min and 40° C. for 10 min and keptat 25° C. to give a double stranded DNA, which was used for the test.

Donor DNA (+ strand having biotin attached to the 5′ terminal) Donor +strand: (SEQ ID NO: 1) 5′-Biotin-ACC CTT TTA GTC AGT GTG GAA AAT CTCTAG CA-3′ Donor − strand: (SEQ ID NO: 2)5′-ACT GCT AGA GAT TTT CCA CAC TGA CTA AAA G-3′ Target DNA (+, −strands both having digoxigenin attached to the 3′ terminal) Target +strand: (SEQ ID NO: 3) 5′-TGA CCA AGG GCT AAT TCA CT-Dig-3′ Target −strand: (SEQ ID NO: 4) 5′-AGT GAA TTA GCC CTT GGT CA-Dig-3′

(iv) Determination of Enzyme (HIV Integrase) Inhibitory Activity

The donor DNA was diluted with TE buffer to 20 nM, of which 50 μL wasadded to each well of streptavidin-coated black plate (manufactured byPIAS Corporation) and allowed to adsorb at 37° C. for 20 min. The platewas washed with phosphate buffer (Dulbecco's PBS, Sanko Junyaku Co.,Ltd.) containing 0.1% Tween 20 and phosphate buffer. Then, an enzymereaction mixture (70 μL), a test substance (10 μL) diluted with theenzyme reaction mixture and 0.75 μM integrase protein (10 μL) were addedto each well and the mixture was reacted at 37° C. for 60 min.composition of enzyme reaction mixture: 30 mM MOPS(3-morpholinopropanesulfonic acid), 5 mM magnesium chloride, 3 mM DTT(dithiothreitol), 0.1 mg/mL BSA (bovine serum albumin), 5% glycerol, 10%DMSO (dimethyl sulfoxide), 0.01% Tween 20.

Then, 25 nM target DNA (10 μL) was added, and the mixture was reacted at37° C. for 20 min and washed with phosphate buffer containing 0.1% Tween20 to stop the reaction.

Then, 100 mU/mL peroxidase labeled anti-digoxigenin antibody solution(Roche, 100 μL) was added, and the mixture was reacted at 37° C. for 60min, followed by washing with phosphate buffer containing 0.1% Tween 20.

Then, peroxidase fluorescence substrate solution (manufactured by PIASCorporation, 100 μL) was added, and the mixture was reacted at roomtemperature for 20 min to 30 min. A reaction quenching liquid(manufactured by PIAS Corporation, 100 μL) was added to discontinue thereaction, and fluorescence intensity at excitation wavelength 325nm/fluorescence wavelength 420 nm was measured.

The HIV integrase inhibitory activity (IC₅₀) of the compound of thepresent invention was calculated from the inhibition rate according tothe following formula:

inhibition rate(%)=[1−(Object-Blank)/(Control-Blank)]×100

-   Object: fluorescence intensity of well in the presence of test    compound-   Control: fluorescence intensity of well in the absence of test    compound-   Blank: fluorescence intensity of well in the absence of test    compound and integrase protein

The results are shown in the following Tables.

TABLE 2-1 inhibitory Example activity No. IC₅₀ (μM) 2 0.013 3 0.0085 40.01 5 0.0074 6 0.0056 7 0.013 8 0.0089 9 0.0091 10 0.0088 11 0.0064 120.0073 13 0.0064 14 0.01 15 0.013 16 0.02 17 0.0079 18 0.0082 19 0.008120 0.017

TABLE 2-2 inhibitory Example activity No. IC₅₀ (μM) 21 0.0094 22 0.00723 0.012 24 0.023 25 0.011 26 0.0076 27 0.01 28 0.015 29 0.01 30 0.00931 0.0083 32 0.0077 33 0.0062 34 0.0082 35 0.0067 36 0.013 37 0.0063 380.012 39 0.01 40 0.013

TABLE 2-3 inhibitory Example activity No. IC₅₀ (μM) 41 0.0072 42 0.003443 0.0046 44 0.0081 45 0.011 46 0.011 47 0.012 48 0.0069 49 0.0051 500.0064 51 0.0057 52 0.013 53 0.01 54 0.0075 55 0.021 56 0.01 57 0.011 580.017 59 0.012 60 0.017

TABLE 2-4 inhibitory Example activity No. IC₅₀ (μM) 61 0.0066 62 0.009263 0.0083 64 0.0061 65 0.013 66 0.0064 67 0.0076 68 0.0098 69 0.013 700.0089 71 0.011 72 0.011 73 0.0077 74 0.0057 75 0.0091 76 0.0083 770.011 78 0.0089 79 0.0064 80 0.0098

TABLE 2-5 inhibitory Example activity No. IC₅₀ (μM) 81 0.0075 82 0.004983 0.0071 84 0.011 85 0.0075 86 0.0095 87 0.0077 88 0.0087 89 0.008 900.0067 92 0.0087 93 0.0078 94 0.0088 95 0.0095 96 0.0067 97 0.0066 980.0075 99 0.0061 100 0.0081 101 0.0064

TABLE 2-6 inhibitory Example activity No. IC₅₀ (μM) 102 0.0071 103 0.018104 0.015 105 0.017 106 0.02 107 0.019 108 0.018 109 0.021 110 0.023 1110.02 112 0.019 113 0.013 114 0.0081 115 0.012 116 0.0096 117 0.0094 1180.013 119 0.011 120 0.015 121 0.016

TABLE 2-7 inhibitory Example activity No. IC₅₀ (μM) 122 0.019 123 0.027124 0.015 125 0.011 126 0.0073 127 0.014 128 0.019 129 0.012 130 0.013131 0.013 132 0.0091 133 0.0074 134 0.016 135 0.012 136 0.011 137 0.0086138 0.011 139 0.012 140 0.0058 141 0.008

TABLE 2-8 inhibitory Example activity No. IC₅₀ (μM) 142 0.0064 1430.0069 144 0.0077 145 0.0056 146 0.0059 147 0.0083 148 0.0098 149 0.0059150 0.0061 151 0.0054 152 0.0059 153 0.0058 154 0.0073 155 0.01 1560.0046 157 0.029 158 0.0054 159 0.0066 160 0.0061 161 0.0078

TABLE 2-9 inhibitory Example activity No. IC₅₀ (μM) 162 0.0071 1630.0077 164 0.0065 165 0.0074 166 0.012 167 0.01 168 0.0058 169 0.012 1700.012 171 0.016 172 0.014 173 0.016 174 0.014 175 0.0095 176 0.0085 1770.017 178 0.02 179 0.019 180 0.01 181 0.014

TABLE 2-10 inhibitory Example activity No. IC₅₀ (μM) 182 0.0097 183 0.01184 0.006 185 0.015 186 0.018 187 0.019 188 0.018 189 0.02 190 0.011 1910.012 192 0.015 193 0.011 194 0.0082 195 0.0059 196 0.0067 197 0.014 1980.0057 199 0.0084 200 0.0096 201 0.0095

TABLE 2-11 inhibitory Example activity No. IC₅₀ (μM) 202 0.013 203 0.013204 0.013 205 0.013 206 0.0059 207 0.024 208 0.012 209 0.012 210 0.023211 0.016 212 0.014 213 0.015 214 0.016 217 0.0053 218 0.0065 219 0.015220 0.0068 221 0.0084 222 0.0065 223 0.012

TABLE 2-12 inhibitory Example activity No. IC₅₀ (μM) 224 0.0073 2250.018 226 0.013 227 0.013 228 0.011 229 0.012 230 0.069 231 0.011 2320.015 233 0.0064 234 0.018 235 0.016 236 0.013 237 0.013 238 0.018 2390.016 240 0.052 241 0.014 242 0.013 243 0.0076

TABLE 2-13 inhibitory Example activity No. IC₅₀ (μM) 244 0.074 2450.0081 246 0.0084 247 0.01 248 0.014 249 0.012 250 0.017 251 0.011 2520.0092 253 0.0077 254 0.0076 255 0.009 256 0.0082 257 0.0091 258 0.0093259 0.009 260 0.012 261 0.011 262 0.01 263 0.009

TABLE 2-14 inhibitory Example activity No. IC₅₀ (μM) 264 0.0085 2650.0093 266 0.011 267 0.011 268 0.015 269 0.0094 270 0.0095 271 0.011 2720.0089 273 0.014 274 0.012 275 0.014 276 0.016 277 0.012 278 0.0099 2790.0063 280 0.016 281 0.016 282 0.015 283 0.018

TABLE 2-15 inhibitory Example activity No. IC₅₀ (μM) 284 0.011 285 0.011286 0.0078 287 0.008 288 0.0088 289 0.01 290 0.014 291 0.0087 292 0.0073293 0.0096 294 0.011 295 0.012 296 0.019

TABLE 2-16 inhibitory Example activity No. IC₅₀ (μM) 297 0.02 298 0.009299 0.0098 300 0.009 301 0.008 302 0.0099 303 0.0058 304 0.0091 3050.0095 306 0.01 307 0.011 308 0.013 309 0.0088 310 0.0099 311 0.0097 3120.012 313 0.0097 314 0.0079 315 0.0088

TABLE 2-17 inhibitory Example activity No. IC₅₀ (μM) 316 0.012 3170.0098 318 0.0065 319 0.0058 320 0.0094 321 0.007 323 0.014

TABLE 2-18 inhibitory Example activity No. IC₅₀ (μM) 327 0.0059 3280.0071 329 0.0061 330 0.0064 331 0.0093 332 0.012 333 0.0075 334 0.0091335 0.0098 336 0.0072 337 0.017 338 0.0071 353 0.013 354 0.0080 3550.0066 356 0.0089 357 0.0073 358 0.012 359 0.0048 360 0.011

TABLE 2-19 inhibitory Example activity No. IC₅₀ (μM) 361 0.015 362 0.010363 0.0087 364 0.010 365 0.012 382 0.0087 383 0.0079 384 0.012 3850.0082 386 0.015 387 0.011 388 0.0086 389 0.014 391 0.024 392 0.011 3930.015 394 0.014 395 0.010 396 0.015 397 0.019

Experimental Example 2 Evaluation of Antiviral Activity

The effect of combined use of the compound of the present invention andexistent anti-HIV agents can be determined in the following manner.

For example, the effect of combined use of two agents from existentnucleoside reverse transcriptase inhibitors (zidovudine, lamivudine,tenofovir), non-nucleoside reverse transcriptase inhibitors (efavirenz)or protease inhibitors (indinavir, nelfinavir) and test substance A andthe like are evaluated using CEM-SS cells infected with HIV-1 IIIB byXTT method.

In addition, the effect of combined use of three agents of testsubstance A, zidovudine and lamivudine, or test substance A, tenofovirand lamivudine, and the like is evaluated.

Prior to the combined use test, IC₅₀ and CC₅₀ of each medicament aloneare measured. 5 concentrates of medicament A and 9 concentrates ofmedicament B, determined based on these results, are combined toevaluate the effect of combined use of two agents. For combined use ofthree agents, a high concentrated medicament B and a medicament C aremixed and medicament A and concentration thereof are combined forevaluation.

The test results of the test substance and concomitant drug alone or incombination thereof are analyzed based on the programs of Prichard andShipman MacSynergy II version 2.01 and Deltagraph version 1.5d. Athree-dimensional plot is drawn from % inhibition at the concentrationsof each combined medicament, the obtained from 3 times of tests, with95% (or 68%, 99%) confidence limits, and the effect of the combined useis evaluated based on the numerical values of μM²% calculated therefrom.The criteria of evaluation are shown in the following.

Definition of interaction μM² % Strong synergistic action >100 Slightsynergistic action +51-+100 Additive action +50-−50  Slight antagonisticaction −51-−100 Strong antagonistic action <−100

Experimental Example 3 Metabolism Stability Test Metabolism StabilityTest in Liver Microsome

Liver microsome of human or animal species (rat or monkey) (manufacturedby Xenotech LLC (Lenexa, Kans., USA), 20 mg protein/mL) (2.5 μL) andNADPH-generating system coenzyme solution (β-nicotinamide adeninedinucleotide phosphate: 5.2 mM, D-glucose-6-phosphate: 13.2 mM,magnesium chloride: 13.2 mM, glucose-6-phosphate dehydrogenase: 1.8U/mL) (50 μL) are suspended in 100 mM potassium phosphate buffer (pH7.4, 147.5 μL), and mixed with a test substance (2 μL) dissolved inacetonitrile containing 0.5% DMSO. After incubation at 37° C. for 0, 10and 60 min, acetonitrile containing formic acid (final concentrated0.1%) is added and the mixture is centrifuged. The test substance(unchanged form) in the supernatant is measured by high performanceliquid chromatography/Mass Spectrometry (LC/MS). The residual ratio (%)is calculated from the obtained measurement values according to thefollowing formula. residual ratio (%)=amount of test substance afterincubation (0, 10 or 60 min)/amount of test substance at incubation 0min×100

Preferred as the compound of the present invention is a compound with aresidual ratio at 60 min later of not less than 40%, more preferably notless than 60%, further preferably not less than 80%.

Formulation Example is given below. This example is merely for theexemplification purpose and does not limit the invention.

Formulation Example

(a) compound of Example 1 10 g (b) lactose 50 g (c) corn starch 15 g (d)sodium carboxymethylcellulose 44 g (e) magnesium stearate  1 g

The entire amounts of (a), (b) and (c) and 30 g of (d) are kneaded withwater, dried in vacuo and granulated. The obtained granules are mixedwith 14 g of (d) and 1 g of (e) and processed into tablets with atableting machine to give 1000 tablets each containing 10 mg of (a).

INDUSTRIAL APPLICABILITY

The compounds of the present invention show a high inhibitory activityagainst HIV integrase.

Therefore, these compounds can be medicaments effective for, forexample, the prophylaxis or treatment of AIDS, as integrase inhibitors,antiviral agents, anti-HIV agents and the like, having an HIV integraseinhibitory activity. In addition, by a combined use with other anti-HIVagent(s) such as protease inhibitor, reverse transcriptase inhibitor andthe like, they can be more effective anti-HIV agents. Furthermore,having high inhibitory activity specific for integrase, they can bemedicaments safe for human body with a fewer side effects.

SEQUENCE LISTING FREE TEXT

-   SEQ ID NO: 1: Donor+ chain for HIV integrase activity measurement-   SEQ ID NO: 2: Donor− chain for HIV integrase activity measurement-   SEQ ID NO: 3: Target+ chain for HIV integrase activity measurement-   SEQ ID NO: 4: Target− chain for HIV integrase activity measurement

1. A compound represented by the following formula [I]or apharmaceutically acceptable salt thereof, or a solvate thereof:

wherein R¹ is (1) a C₁₋₆ alkyl group optionally substituted by the sameor different 1 to 5 substituents selected from (i) a C₃₋₈ cycloalkylgroup, and (ii) a C₁₋₆ alkoxy group, (2) a C₃₋₈ cycloalkyl group, or (3)a saturated monocyclic heterocyclic group containing, besides carbonatom, 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atomand a sulfur atom, R², R³, R⁴ and R⁵ are the same or different and eachis (1) a hydrogen atom, (2) a carboxyl group, (3) —CO—NR^(a)R^(b)wherein R^(a) and R^(b) are the same or different and each is (i) ahydrogen atom, (ii) a C₁₋₆ alkyl group optionally substituted by thesame or different 1 to 5 substituents selected from the following groupB, or (iii) a C₃₋₈ cycloalkyl group, or R^(a) and R^(b) optionally form,together with the nitrogen atom bonded thereto, a saturated monocyclichetero ring optionally containing, besides carbon atom and one nitrogenatom, 1 to 5 hetero atoms selected from a nitrogen atom, an oxygen atomand a sulfur atom, and optionally substituted by the same or different 1to 5 substituents selected from the following group B, (4) a C₁₋₆ alkylgroup optionally substituted by the same or different 1 to 5substituents selected from the following group A, or (5) a cyano group,or R² and R³, or R⁴ and R⁵ optionally form, together with the carbonatom bonded thereto, i) C₃₋₈ cycloalkane, or ii) a saturated monocyclichetero ring containing, besides carbon atom, 1 to 6 hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom, whereinR², R³, R⁴ and R⁵ are not hydrogen atoms at the same time, R⁶ is (1) aC₁₋₆ alkyl group optionally substituted by the same or different 1 to 5halogen atoms, (2) a C₁₋₆ alkoxy group, (3) a halogen atom, or (4) aC₃₋₈ cycloalkyl group, Y is a nitrogen atom, m is an integer of 1 to 5,and when m is an integer of 2 to 5, then each R⁶ may be the same ordifferent, and n is an integer of 1 to 3, and wherein group A isselected from (a) —CO—NR^(A1)R^(A2) wherein R^(A1) and R^(A2) are thesame or different and each is (i) a hydrogen atom, (ii) a C₁₋₆ alkylgroup optionally substituted by the same or different 1 to 5substituents selected from the following group B, or (iii) a C₃₋₈cycloalkyl group, or R^(A1) and R^(A2) optionally form, together withthe nitrogen atom bonded thereto, a saturated monocyclic hetero ringoptionally containing, besides carbon atom and one nitrogen atom, 1 to 3hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom, and optionally substituted by the same or different 1 to 5substituents selected from the following group B, (b) a hydroxyl group,(c) a C₁₋₆ alkoxy group, (d) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group, (e) acyano group, (f) —NR^(A3)R^(A4) wherein R^(A3) and R^(A4) are the sameor different and each is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group,(iii) a C₁₋₆ alkyl-carbonyl group, or (iv) a C₁₋₆ alkyl-sulfonyl group,or R^(A3) and R^(A4) optionally form, together with the nitrogen atombonded thereto, a hetero ring optionally containing, besides carbon atomand one nitrogen atom, 1 to 5 hetero atoms selected from a nitrogenatom, an oxygen atom and a sulfur atom, and optionally substituted by 1or 2 oxo groups, (g) a carboxyl group, (h) a C₁₋₆ alkyl-sulfonyl group,and (i) a C₁₋₆ alkyl-carbonyl group; and group B is selected from (a) ahydroxyl group, (b) a C₁₋₆ alkoxy group, (c) a C₁₋₆ alkoxy-C₁₋₆ alkylgroup (d) a C₃₋₈ cycloalkyl group, and (e) an oxo group.
 2. The compoundaccording to claim 1, wherein R¹ is a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected from(i) a C₃₋₈ cycloalkyl group, and (ii) a C₁₋₆ alkoxy group, or apharmaceutically acceptable salt thereof, or a solvate thereof.
 3. Thecompound according to claim 2, wherein R¹ is a C₁₋₆ alkyl group, or apharmaceutically acceptable salt thereof, or a solvate thereof.
 4. Thecompound according to claim 2, wherein R¹ is a C₁₋₆ alkyl groupsubstituted by a C₃₋₈ cycloalkyl group, or a pharmaceutically acceptablesalt thereof, or a solvate thereof.
 5. The compound according to claim1, wherein R¹ is a C₃₋₈ cycloalkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof,
 6. The compound accordingto claim 1, wherein one of R², R³, R⁴ and R⁵ is —CO—NR^(a)R^(b) whereinR^(a) and R^(b) are the same or different and each is (i) a hydrogenatom, (ii) a C₁₋₆ alkyl group optionally substituted by the same ordifferent 1 to 5 substituents selected from group B, or (iii) a C₃₋₈cycloalkyl group, or R^(a) and R^(b) optionally form, together with thenitrogen atom bonded thereto, a saturated monocyclic hetero ringoptionally containing, besides carbon atom and one nitrogen atom, 1 to 5hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom, and optionally substituted by the same or different 1 to 5substituents selected from group B, or a pharmaceutically acceptablesalt thereof, or a solvate thereof.
 7. The compound according to claim1, wherein one of R², R³, R⁴ and R⁵ is a C₁₋₆ alkyl group optionallysubstituted by the same or different 1 to 5 substituents selected fromgroup A, or a pharmaceutically acceptable salt thereof, or a solvatethereof.
 8. The compound according to claim 1, wherein R⁶ is a halogenatom, or a pharmaceutically acceptable salt thereof, or a solvatethereof.
 9. (canceled)
 10. (canceled)
 11. The compound according toclaim 1, wherein m is 1 or 2, or a pharmaceutically acceptable saltthereof.
 12. The compound according to claim 1, wherein n is 1, or apharmaceutically acceptable salt thereof, or a solvate thereof.
 13. Thecompound according to claim 1, which is represented by the followingformula [I-1], or a pharmaceutically acceptable salt thereof, or asolvate thereof:

wherein R¹¹ is (1) a C₁₋₆ alkyl group optionally substituted by the sameor different 1 to 5 substituents selected from (i) a C₃₋₈ cycloalkylgroup, and (ii) a C₁₋₆ alkoxy group, or (2) a C₃₋₈ cycloalkyl group,R²¹, R³¹, R⁴¹ and R⁵¹ are the same or different and each is (1) ahydrogen atom, (2) —CO—NR^(a)R^(b) wherein R^(a) and R^(b) are the sameor different and each is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl groupoptionally substituted by the same or different 1 to 5 substituentsselected from group B, or (iii) a C₃₋₈ cycloalkyl group, or R^(a) andR^(b) optionally form, together with the nitrogen atom bonded thereto, asaturated monocyclic hetero ring optionally containing, besides carbonatom and one nitrogen atom, 1 to 5 hetero atoms selected from a nitrogenatom, an oxygen atom and a sulfur atom, and optionally substituted bythe same or different 1 to 5 substituents selected from group B, or (3)a C₁₋₆ alkyl group optionally substituted by the same or different 1 to5 substituents selected from group A, wherein R²¹, R³¹, R⁴¹ and R⁵¹ arenot hydrogen atoms at the same time, R⁶¹ is a halogen atom, and R⁶² is ahydrogen atom or a halogen atom.
 14. The compound according to claim 13,wherein R²¹ is a C₁₋₆ alkyl group optionally substituted by the same ordifferent 1 to 5 substituents selected from group A, and R³¹, R⁴¹ andR⁵¹ are each a hydrogen atom, or a pharmaceutically acceptable saltthereof, or a solvate thereof.
 15. The compound according to claim 13,wherein R²¹ is a C₁₋₆ alkyl group, and R³¹, R⁴¹ and R⁵¹ are each ahydrogen atom, or a pharmaceutically acceptable salt thereof, or asolvate thereof.
 16. The compound according to claim 13, wherein R⁴¹ isa C₁₋₆ alkyl group optionally substituted by the same or different 1 to5 substituents selected from group A, and R²¹, R³¹ and R⁵¹ are each ahydrogen atom, or a pharmaceutically acceptable salt thereof, or asolvate thereof.
 17. The compound according to claim 13, wherein R²¹ isa C₁₋₆ alkyl group optionally substituted by the same or different 1 to5 substituents selected from group A, R⁴¹ is a C₁₋₆ alkyl group, and R³¹and R⁵¹ are each a hydrogen atom, or a pharmaceutically acceptable saltthereof, or a solvate thereof.
 18. (canceled)
 19. (canceled)
 20. Thecompound according to claim 1, which is represented by the formula:

or a pharmaceutically acceptable salt thereof, or a solvate thereof. 21.The compound according to claim 1, which is represented by the formula:

or a pharmaceutically acceptable salt thereof, or a solvate thereof. 22.The compound according to claim 1, which is represented by the formula:

or a pharmaceutically acceptable salt thereof, or a solvate thereof. 23.The compound according to claim 1, which is represented by the formula:

or a pharmaceutically acceptable salt thereof, or a solvate thereof. 24.The compound according to claim 1, which is represented by the formula:

or a pharmaceutically acceptable salt thereof, or a solvate thereof. 25.The compound according to claim 1, which is represented by the formula:

or a pharmaceutically acceptable salt thereof, or a solvate thereof. 26.The compound according to claim 1, which is represented by the formula:

or a pharmaceutically acceptable salt thereof, or a solvate thereof. 27.The compound according to claim 1, which is represented by the formula:

or a pharmaceutically acceptable salt thereof, or a solvate thereof. 28.The compound according to claim 1, which is represented by the formula:

or a pharmaceutically acceptable salt thereof, or a solvate thereof. 29.The compound according to claim 1, which is represented by the formula:

or a pharmaceutically acceptable salt thereof, or a solvate thereof. 30.A pharmaceutical composition comprising the compound according to claim1 or a pharmaceutically acceptable salt thereof, or a solvate thereof,and a pharmaceutically acceptable carrier.
 31. An anti-HIV agentcomprising the compound according to claim 1 or a pharmaceuticallyacceptable salt thereof, or a solvate thereof, as an active ingredient.32. An HIV integrase inhibitor comprising the compound according toclaim 1 or a pharmaceutically acceptable salt thereof, or a solvatethereof, as an active ingredient.
 33. An anti-HIV agent comprising thecompound according to claim 1 or a pharmaceutically acceptable saltthereof, or a solvate thereof, in combination with one or more otherkinds of anti-HIV active substances.
 34. (canceled)
 35. (canceled)
 36. Amethod for the prophylaxis or treatment of an HIV infectious disease ina mammal, which comprises administering an effective amount of thecompound according to claim 1 or a pharmaceutically acceptable saltthereof, or a solvate thereof, to said mammal.
 37. The method accordingto claim 36, which further comprises administering an effective amountof one or more other kinds of anti-HIV active substances to the mammal.38. A method for inhibiting HIV integrase in a mammal, which comprisesadministering an effective amount of the compound according to claim 1or a pharmaceutically acceptable salt thereof, or a solvate thereof, tosaid mammal.
 39. An anti-HIV composition comprising the compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof, or asolvate thereof, and a pharmaceutically acceptable carrier.
 40. Apharmaceutical composition for inhibiting HIV integrase, comprising thecompound according to claim 1 or a pharmaceutically acceptable saltthereof, or a solvate thereof, and a pharmaceutically acceptablecarrier.
 41. A commercial package comprising the pharmaceuticalcomposition according to claim 30 and a written matter associatedtherewith, which states that the pharmaceutical composition can orshould be used for treating HIV,
 42. A kit comprising the pharmaceuticalcomposition according to claim 30 and a written matter associatedtherewith, which states that the pharmaceutical composition can orshould be used for treating HIV.
 43. A pharmaceutical compositionaccording to claim 30, which further comprises one or more otheranti-HIV active substances.